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URIC  ACID 

The   Chemistry,   Physiology,  and 
Pathology   of  Uric  Acid 


AND   THE 


Physiologically  Important  Purin  Bodies 

WITH    A   DISCUSSION  OF 

THE  METABOLISM  IN   GOUT 


BY 


FRANCIS    H.    McCRUDDEN 


^ 


Zift  JFort  t^ni  ^tess 

SAMUEL  USHER 

176  TO  184  HIGH    STREET 

BOSTON.  MASS. 


7-1^-  2.0/  3  / 


Copyright,  1905, 
By  Francis  H.  McCrudden. 


INTRODUCTION 


FoxjR  years  ago  the  author  began  a  study  of  the  metaboUsm  in  certain 
chronic  bone  diseases,  —  rheumatoid  arthritis,  osteo-arthritis,  osteitis  deform- 
ans, etc.,  —  under  the  direction  of  Doctors  Goldthwait,  Painter  and  Osgood, 
of  Boston.  After  some  prehminary  chemical  work  it  seemed  advisable  to 
make  a  very  thorough  study  of  the  literature  concerning  the  metabolism  of 
the  inorganic  elements,  and  also  of  uric  acid,  since  in  the  opinion  of  certain 
writers  uric  acid  is  of  great  importance  in  the  etiology  of  the  rheumatic  dis- 
eases. The  results  of  this  study  led  to  the  conclusion  that  rheumatic 
diseases  and  uric-acid  metabolism  do  not,  at  the  present  time,  seem 
to  be  closely  related.  The  fact  that  many  English  writers  do  not  agree 
with  this  conclusion,  and  that  there  is  no  complete  and  reliable  account 
of  the  metabolism  of  uric  acid  to  be  found  in  one  place,  made  it  seem 
advisable   to  publish  the  results  of  the  work. 

The  view  of  Haig,^  the  foremost  of  those  who  attribute  to  uric  acid  a  great 
pathological  importance,  may  be  seen  from  the  following  extracts.  On  page 
10  he  sa3's:  "  Uric  acid  affects  not  only  the  blood,  but  influences  in  a  similar 
way  the  functions,  nutrition,  and  eventually  the  structure  of  every  organ  and 
tissue  in  the  body,  and  as  regards  infectious  diseases  has,  in  some  cases,  a 
more  important  influence  than  the  microbes  themselves.  As  regards  the 
tissues,  it  con,trols  the  production  of  energy  and  the  production  of  heat  to 
an  extent  which,  acting  as  it  does  from  bone  to  bone  throughout  the  whole 
of  life,  cannot  but  be  of  enormous  importance!  But  more  recent  advances 
have  carried  us  far  beyond  this,  and  we  can  now  say  with  absolute  certainty 
that  uric  acid  controls  and  conditions  the  capillary  circulation  of  tlie  whole 
body,  .  .  .  and  thus  regulates  the  blood  pressure,  the  heart  action,  the 
nutrition  of  the  heart  and  vessels,  the  nutrition  of  the  tissue,  and  all  the  meta- 
bolic phenomena  which  constitute  the  life  of  tlie  body  to  its  minutest  cells." 
And  again,  on  page  168,  he  saj^s:  "  Uric  acid  really  dominates  the  function, 
nutrition,  and  structure  of  the  human  body,  to  an  extent  which  has  never  yet 
been  dreamed  of  in  our  philosophy,  and  in  place  of  affecting  the  structure  of 
a  few  comparatively  insignificant  fibrous  tissues  in  which  it  is  found  after 

1  A.  Haig.     Uric  Acid  as  a  Factor  Lq  the  Causation  of  Disease.     6th  ed.,  1903. 

iii 


iv  Introduction 

death,  it  may  really  direct  the  development,  life,  history,  and  final  decay  and 
dissolution  of  every  tissue,  from  the  most  important  nerve  centers  and  the 
most  active  glands,  to  the  matrix  of  the  nails  and  the  structure  of  the  skin 
and  hair." 

I  think  any  one  who  reads  this  book  cannot  but  come  to  the  conclusion 
that  Haig's  views  are  entirely  unwarranted. 

The  time,  too,  seemed  ripe  for  such  a  publication.  Although  the  metabo- 
lism of  uric  acid  is  by  no  means  completely  understood  at  the  present 
moment,  yet  several  researches  have  recently  been  carried  out  which  settle 
many  points  of  fundamental  importance  in  the  theory  of  uric-acid  metabolism 
and  gout.  Therefore,  it  seemed  advisable  to  define  the  present  status  of  the 
subject.  Among  these  researches  may  be  mentioned  the  two  publications 
of  Burian  and  Schur  in  1901.  These  authors  have  shown  quantitatively  that 
it  is  the  purin  bodies  of  the  food,  either  free  or  combined  in  nuclein,  and  only 
the  purin  bodies,  that  have  any  influence  on  the  excretion  of  exogenous 
uric  acid.  They  also  showed  quantitatively  the  relative  importance  of  the 
endogenous  and  exogenous  uric  acid.  Fischer's  paper  on  the  purin  bodies  in 
1899,  makes  clear  why  the  purin  bases  should  be  of  such  importance  in  uric 
acid  metabolism.  His  has  recently  applied  the  methods  of  the  science  of 
physical  chemistry  to  the  determination  of  the  behavior  of  uric  acid  in  solu- 
tion. As  a  result  of  his  work,  many  of  the  old  views  concerning  the  solubility 
of  uric  acid  in  water  and  in  the  urine,  and  the  effects  of  alkalies  and  other 
agents  on  the  solubility  of  uric  acid,  have  been  overthrown.  Physical  chem- 
istry has  taught  us  that  the  acidity  and  the  alkalinity  of  many  solutions  of 
complex  mixtures  of  electrolytes  such  as  blood  and  urine  cannot  be  deter- 
mined by  titration  methods.  Only  recently  has  an  accurate  method  been 
offered  by  which  we  could  determine  the  acidity  of  the  urine  and  the  alkalinity 
of  the  blood.  By  means  of  this  method  Hober  has  shown  that  the  prevailing 
views  concerning  the  acidity  of  the  urine  and  the  alkalinity  of  the  blood  are 
far  from  correct.  The  work  of  His  and  Hober,  taken  together,  puts  an  end 
to  many  theories  concerning  uric  acid  in  the  blood  and  urine,  and  to  any 
scientific  basis  for  the  alkali  therapeutics  in  gout.  Another  point  of  import- 
ance only  recently  established  bj^  Burian  and  Schur,  Soetbeer  and  Ibrahim 
and  Salkowski,  is  the  fact  that  uric  acid  is  excreted  in  great  part  unchanged  by 
man.  This  is  certainly  a  final  death-blow  to  the  old  view  that  uric  acid  is  an 
antecedent  of  urea  in  the  destructive  metabolism  of  proteid. 

I  have  made  a  thorough  study  of  the  pure  chemistry  of  uric  acid,  and  of 
its  decomposition  products,  and  of  those  purin  bodies  which  have  physio- 
logical importance;  of  the  behavior  of  uric  acid  in  solutions  of  pure  water; 
in  the  solution  of  simple  and  mixed  electrolytes,  and  of  organic  compoimds; 


Introduction  v 

and  in  the  urine  and  blood.  I  have  attempted  to  study  all  the  research 
that  has  been  done  on  the  physiology  of  uric  acid,  the  effects  of  food,  and  of 
the  qualitative  and  quantitative  change  in  the  food,  the  effects  of  alcohol, 
exercise  and  other  physiological  functions,  and  also  the  research  on  uric 
acid  in  pathological  conditions  of  all  kinds,  especially  in  gout.  I  have  also 
studied  the  work  on  the  general  metabolism  in  gout. 

I  have  arranged  the  material  systematically,  going  from  the  simple  facts 
of  the  pure  chemistry  of  the  purin  bodies  to  gradually  more  complex  condi- 
tions of  metabolism,  so  that  by  the  time  the  section  on  the  metabolism  in 
gout  has  been  reached,  all  the  facts  upon  which  different  theories  of  gout'are 
based  have  already  been  treated  in  the  proper  place.  I  have  adhered  closely 
to  an  exact  statement  of  experimental  data  throughout,  and  have  ventured 
in  but  few  cases  to  propound  a  theoretical  explanation  of  the  facts,  relying 
on  the  arrangement  of  the  facts  themselves  to  bring  out  the  explanation. 

I  wish  to  thank  Doctors  Goldthwait,  Painter  and  Osgood,  who  have  under- 
taken all  the  expenses  of  the  preparation  and  publication  of  this  work. 

FRANCIS  H.  McCRUDDEN, 

Laboratory  of  Physiological  Chemistry, 
Harvard  Medical  School. 
August,  1905. 


Digitized  by  tine  Internet  Arciiive 

in  2010  witii  funding  from 

Open  Knowledge  Commons  (for  the  Medical  Heritage  Library  project) 


http://www.archive.org/details/uricacidchemistrOOmccr 


CONTENTS 


I.  CHEMISTRY 

PAGE 

General  Chemical  Behavior  of  Uric  Acid,  the  Purin  Bases,  and 

THE   MoNOUREi'DES 1 

HISTORICAL 1 

The  General  Chemistry  of  the  Purins 1 

Work  of  Scheele 1 

From  Scheele  to  Liebig 2 

Work  of  Liebig  and  Wohler 3 

From  Liebig  to  Emil  Fischer 4 

STRUCTURE  AND  SYNTHESIS  OF  THE  PURINS  ...  5 

Structure     5 

Synthetical  Methods 9 

Synthesis  of  Uric  Acid  from  Pseudouric  Acid    ...    .  9 

Alkylating  of  the  Oxy purins 10 

Preparation  of  the  Chlor  Purins 10 

Change  of    the  Halogen  Purins  into  Oxy-   Thio-  and 

Amino-Purins 11 

The  Reduction  of  the  Halogens 12 

The  Special  Chemistry  of  the  Members  of  the  Purin  Group    ...  12 

TRIOXYPURIN  (URIC  ACID)  AND  DERIVATIVES     .    .  12 

Occurrence 12 

Synthesis 1'^ 

Decomposition  and  Oxidation 20 

Reduction 24 

Relation  of  Uric  Acid  to  Other  Members  of  the 

Group 25 

Preparation 26 

Qualitative  Tests 27 

Quantitative  Determination 27 

The  Methyl  Uric  Acids 28 

DIOXYPURIN  and  derivatives 28 

Xanthin 28 

Heteroxanthin 30 

1-Methyl-Xanthin 31 

Theobromin 31 

Theophyllin 33 

Paraxanthin 34 

Capfein 36 

vii 


viii  Contents 

PAGE 

MONOXYPURIN  AND  DERIVATIVES 40 

Hypoxanthin 40 

AMINO-PURINS 41 

Adenin 41 

GUANIN ' 43 

7-Methyl  Guanin 45 

PURIN 45 

THE  MONOUREIDES 45 

Solubility  of  Uric  Acid  and  Urates 48 

In  Aqueous  Solution 48 

URIC  ACID      48 

In  Pure  Water 48 

Effect  of  Acids  upon  the  Solubility  of  Uric   Acid  51 

Amorphous  and  Crystalline  Uric  Acid 54 

THE  URATES  AND  COMPOUNDS  OF  URIC  ACID   .    .  55 

The  Neutral  Urates 56 

The  Acid  Urates 56 

The  Quadriurate 63 

Compounds  op  Uric  Acid  with  Urea  and  Kreatin     .    .  69 
Compounds  of  Uric  Acid  with  Nucleic  and  Thymic 

Acids  and  Formaldehyde 69 

In  the  Urine 71 

In  the  Blood 88 

n.  PHYSIOLOGY 

In  Birds 92 

The  Nitrogenous  Metabolism  in  Birds 93 

The  Organ  of  Formation  of  Uric  Acid  in  Birds 94 

Uric  Acid  Formed  by  Synthesis  in  Birds 96 

Uric  Acid  Formed  by  Oxidation  in  Birds      102 

In  Mammals 103 

Formation  of  Uric  Acid  in  the  Body 103 

FROM   NUCLEO-PROTEIDS,   NUCLEINS,   AND  PURIN 

BODIES 104 

The  Chemistry  and  Occurrence  of  the  Nucleoproteids  and 

Purins 104 

The    Physiological   Relation    between    the   Nucleoproteids, 

Nucleins,  Nucleic  Acid,  and  Purin  Bases  and  Uric  Acid,  112 

Historical:  The  Source  of  Uric  Acid 112 

Uric  Acid  from  the  Nucleoproteids  and  Purins 

of  the  Body 119 

Uric  Acid  frojn  the  Leucocytes      119 

Uric  Acid   from  Cells  other  than  the  Leucocytes,  131 

From  Muscular  Activity 132 


Contents  ix 


PAGE 


nucleins  and  purin  bodies  of  the  food  as  a 
Source  of  the  Uric    Acid  and  Purin  Bodies 

Excreted 134 

The  Relative  Quantity  of  Uric  Acid  from  the 

Food  and  that  from  the  Body  Tissues     .    .    .  142 

The  Endogenous  Uric  Acid 143 

Uric  Acid  from  Purin  Bodies  of  the  Food   .    .    .  148 

Absorption  of  Nuclein  and  Purin  Bodies 149 

Purin  Bodies  of  the  Feces 150 

The  Metabolism  of  the  Individual  Purin  Bodies 154 

Hypoxanthin 154 

Xanthin 156 

Adenin 157 

GUANIN 158 

Uric  Acid      160 

The  Methyl  Purins 162 

Caffein 162 

Theobromin 164 

Other  Methyl  Purins 165 

Effect  of  Methyl  Purins  on  the  Excretion  of  Uric 

Acid 165 

FROM  PROTEID 166 

SYNTHESIS  OF  URIC  ACID  IN  THE  BODY 171 

From  Glycocoll  and  Urea 171 

From  Lactic  Acid  and  Urea 177 

From  Glycerin  and  Urea 178 

From  the  Monoureides  and  Urea 178 

From  Other  Compounds 180, 

Decomposition  of  Uric  Acid  in  the  Body 186 

DECOMPOSITION  PRODUCTS  OF  URIC  ACID  OUTSIDE 

THE  BODY 187 

IN  RABBITS 188 

Early  Work 188 

Absorption  and  Excretion  as  Uric  Acid  or  Urea 189 

Oxidation  to  Allantoin,  Oxalic  Acid,  Oxaluric  Acid,  Alloxan, 

Alloxantin,  and  Parabanic  Acid      190 

Oxidation  to  Glycocoll 191 

Summary 192 

IN  DOGS  AND  CATS 193 

Early  Work 193 

Absorption  a7id  Excretion  as  Uric  Acid  and  Urea     ....  193 

Oxidation  to  Allantoin 195 

Oxidation  to  Oxalic  Acid 198 

Oxidation   to   Parabanic   Acid,   Alloxan,    Alloxantin,   and 

.  Glycocoll 199 

Summary 200 


X  Contents 

PAGE 

IN  MAN 200 

Early  Work 200 

Excretion  as  Uric  Acid 201 

Oxidation  to  Oxalic  Acid 202 

Oxidation  to  Allantoi?i  and  Gh/cocoll 206 

Summary 206 

Organ  of  Formation      207 

THE  KIDNEYS 207 

THE  SPLEEN 211 

CARTILAGE,    CELLS     OF    THE    DIGESTIVE    TRACT, 

DIGESTIVE  GLANDS,  AND  MUSCLES     .......  214 

THE  LIVER 215 

Summary 218 

Organ  of  Decomposition      219 

IN  CARNIVORA 219 

IN  OTHER  MAMMALS 223 

Summary' ,    .  225 

Effect  op  Drugs  on  the  Uric  Acid  Excretion 226 

Effect  of  Drugs  on  the  Solubility  of  Uric  Acid  in  the  Urine  ....  227 
Effect  of  Drugs  on  the  Solubility  of  Uric  Acid  in  the  Blood     .    .  235 
'              EFFECT   OF   ALKALIES   ON   THE   URIC  ACID  CON- 
CRETIONS  IN    BIRDS 239 

Effect  of  Drugs  on  the  Quantity  of  the  Uric  Acid  Excretion    .    .  240 

ALKALIES 241 

WATER  AND  NEUTRAL  SALT  SOLUTIONS 244 

SALICYLIC  ACID 245 

QUINIC  ACID 247 

ALCOHOL 249 

COLCHICUM 251 

ANTIPYRIN,  ANTIFEBRIN,  AND  PHENACETIN   ...  252 

QUININE      , 253 

TANNIC  ACID  AND  TANNIN      254 

LEAD 254 

OTHER  DRUGS 255 

BATHS 256 

IIL  PATHOLOGY 

Action  of  Uric  Acid  and  the  Purins  in  the  Body 258 

General  Action      258 

Structural  Changes  Due  to  Purin  Bodies 260 

EFFECT  OF  PURIN  BASES 260 


Contents  xi 

PAGE 

EFFECT  OF  URIC  ACID ^   .  261 

In  Birds     ' 261 

In  Mammals 264 

Gout 269 

Analysis  of  Concretions 269 

Uric  Acid  in  the  Blood 270 

Alkalinity  of  the  Blood  in  Gout 272 

Solubility  of  Uric  Acid  in  the  Blood  and  Tissues 273 

Metabolism  in  Gout 275 

METABOLISM  OF  URIC  ACID 275 

METABOLISM  OF  PURIN  BASES 278 

METABOLISM  OF  NITROGEN  AND  FAT 279 

METABOLISM  OF  PHOSPHORUS,  POTASSIUM,  ETC.   .    .  282 

Causes  of  Increased  Uric  Acid  in  the  Blood  in  Gout 284 

INCREASED  FORMATION 284 

RETENTION 286 

DECREASED  DESTRUCTION  . 290 

CHANGE  IN  CHEMICAL  COMBINATION 292 

Cause  of  Formation  of  Concretions 292 

CHEMICAL  THEORIES 292 

NERVOUS  THEORIES 300 

Cause  of  Acute  Attack 301 

Uric  Acid  Infarcts 303 

Other  Diseases 305 


THE  CHEMISTRY,  PHYSIOLOGY,  AND 
PATHOLOGY  OF  URIC  ACID 


I.  XHe  P\ire  CHemistry  of  Uric  Acid  and  Some 
of  tKe  PKysiolo^ically  Important  Pxirin 
Bases 


PuEiN  and  its  derivatives  have  been  called  the  nuclein  bases 
by  Kossel,  the  alloxuric  bases  by  Kriiger.  The  two  latter  have 
called  the  bases  and  uric  acid  together  the  alloxuric  bodies. 
Fischer  calls  them  all  purin  bodies,  and  this  is  probably  the  most 
common  name  for  them  now. 

Since  uric  acid  and  the  purin  bases  have  been  thought  to  be 
intimately  connected  with  the  subject  of  gout  and  the  uric  acid 
diathesis,  it  is  of  importance  first  to  know  something  about  the 
chemistry  of  these  bodies. 

Genekal  Chemical  Behavior  of  Uric  Acid  and  Purin  Bases 

The  General  Chemistry  of  the  Purins 

HISTORICAL 

The  Work  of  Scheele.  —  Uric  acid  was  discovered  in  1776 
in  bladder  stones  and  human  urine  by  Scheele.^  He  showed 
its  acid  nature  by  dissolving  it  in  alkali  and  lime  water.  He 
obtained  it  pure  by  precipitation  from  its  salts  with  weak 
acids.  On  dry  distillation,  carbon,  ammonium  carbonate,  and  a 
volatile  acid  gas  (cyanuric  acid),  easily  soluble  in  water,  were 
obtained.  Boiling  hydrochloric  acid  had  no  action  on  it.  Strong 
sulphuric  acid  decomposed  it  with  formation  of  carbon  dioxide 
and  sulphur  dioxide.  Silver  nitrate  gave  a  black  precipitate 
with  an  alkaline  urate.     Nitric  acid  or  aqua  regia  dissolved  the 

*  K.  W.  Scheele.  Examen  chemicum  Calculi  urinarii.  Opuscular  II,  73.  Also,  Lorenz 
Crell.     Die  neuesten  Entdeckungen  in  der  Chemie,  III,  227. 


2         The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

acid  with  effervescence.  These  are  the  most  important  changes 
which  uric  acid  undergoes. 

From  Scheele  to  Liebig.  —  At  the  same  time  and  inde- 
pendently of  Scheele,  Bergmann  ^  found  uric  acid  in  bladder 
stones. 

Fourcroy  ^  studied  the  physical  properties  of  uric  acid  more 
accurately  and  named  it  first  acide  lithique,  and  later  acid  urique. 
He  was  the  first  ^  to  find  that  chlorine  water  changes  uric  acid  to 
urea,  and  observed  the  formation  of  hydrocyanic  acid  by  the 
distillation  of  uric  acid. 

The  discovery  of  uric  acid  in  gouty  concretions  was  made 
by  Pearson,*  although  Neumeister  ^  credits  the  discovery  to 
WoUaston. 

Somewhat  later,  Fourcroy  and  Vauquelin  ^  found  it  in  the 
excrement  of  birds.  Guano  is  still  the  cheapest  source  for  the 
preparation  of  this  acid. 

In  1815  William  Prout '  found  the  excrement  of  the  boa  con- 
strictor to  consist  of  90  per  cent  uric  acid  partly  combined  with 
ammonia  and  potassium.  Since  then  serpent  excrements  have 
furnished  the  best  source  for  obtaining  small  amounts  of  uric 
acid. 

In  1817  "  xanthin  oxyd  "  (xanthin)  was  discovered  in  bladder 
stones  by  Marcet.^ 

In  1820,  Runge,^  and  in  1821,^°  Robiquet,  Pelletier,  and  Caven- 
tou  discovered  caffein.     Thein  was  discovered  by  Oudrey  "  in  tea 

1  T.  Bergmann.  Opuscular,  IV,  387.  And  Crell.  Die  neuesten  Entdeckungen  in  der 
Chemie,  III,  232. 

2  A.  Fourcroy.  Annales  de  Chimie,  16,  113  (1793).  Suite  de  L'Analyse.  Comparee 
des  diff^rents  espfeces  de  Concretions  animales  et  v^g^tales:  tir^e  du  Dictionnaire  encyclo- 
pedique,  art,  calculs.  And  Examen  des  experiences  et  des  observations  nouvelles  de  M.  G. 
Pearson  sur  les  Concretions  urinaircs  de  Thomme  et  comparison  des  resultats  obtenus  par 
ce  chimiste  avec  coux  de  Scheele,  de  Bergmann,  et  de  quelque  chimistes  francais.  Annales 
de  Chimie,  27,  225  (1798). 

5  Annales  du  Museum,  1,  98  (1802).  Sur  le  nombre,  la  nature,  et  les  caractfere  distinctifs 
des  differents  materiaux  qui  forment  des  calculs,  les  b^zoards  et  les  di verses  concretions  des 
animaux. 

*  Pearson.     Philosophical  Transactions  of  the  Royal  Society,  London.     15  (1798). 

^  Neumeister.     Lehrbuch  der  physiologische  Chemie.     2t  Aufl.,  681. 

8  Fourcroy  et  Vauquehn.  Annales  de  Chimie,  56,  258  (1805).  Sur  le  guano  ou  sur 
I'engrais  natural  des  ilots  de  la  mer  du  Sud  prfes  des  cotes  du  Perou. 

'  Thomson.  Annals  of  Philosophy,  5,  413.  Analysis  of  the  Excrements  of  the  Boa 
Constrictor. 

'  An  Essay  on  the  Chemical  History  of  Calcal  Disorders.     London,  1817. 

^  Pamge.     Phyto-chemische  Entdeckungen.     Berlin,  1820. 

•"Berzelius  Jahresberichte,  4,  180  (1825),  and  7,  269  (1828). 

"  Oudrey.     Thein,  eine  organische  Salzbase  in  Thee.     Mag.  fiir  Pharm.,  19,  49  (1827). 


Chemistry  3 

in  1827,  and  thein  and  caffein  were  shown  to  be  identical  by 
Jobst  ^  in  1838. 

Prout  and  Brugnatelli  ^  studied  carefully  the  decomposition  of 
uric  acid  by  nitric  acid  and  discovered  a  colorless  crystalline 
compound  (alloxan)  which  they  called  acido-ossieritrico. 

In  1829,  Wohler  ^  showed  the  identity  of  the  acid  which  Scheele 
had  obtained  by  the  dry  distillation  of  uric  acid  and  which  had 
been  called  brenzblasensteinsaure  or  brenzuric  acid  (pyrouric  acid) 
with  the  cyanuric  acid  prepared  b}^  Serullas*  out  of  cyanuric 
chloride  and  confirmed  the  view  of  Fourcroy  and  Vauquelin  ^  that 
urea  was  formed  at  the  same  time.  He  found  that  about  half 
the  distillate  consists  of  urea  and  about  half  of  cyanuric  acid. 

Liebig  ^  and  Mitscherlich  ^  at  about  the  same  time  first  showed 
the  elementary  formula  of  uric  acid  to  be  CgH^N^Og. 

The  Work  of  Liebig  and  Wohler.  —  From  1834  to  1838 
Liebig  and  Wohler  worked  together  on  uric  acid.  By  oxidation 
with  lead  peroxide  they  showed  the  change  of  uric  acid  to  allantoin, 
which  substance  had  already  been  found  in  the  amniotic  fluid  of 
the  cow.^  They  showed  the  change  of  uric  acid  to  alloxan  by 
moderate  oxidation,  which  had  been  previously  described  by 
Brugnatelli,  and  determined  its  composition  by  accurate  analysis. 
They  obtained  and  to  some  extent  studied  the  properties  of  alloxan, 
alloxantin,  dialuric  acid,  alloxanic  acid,  thiouric  acid,  uramil, 
parabanic  acid,  oxaluric  acid,  mesoxalic  acid,  mycomelinic  acid, 
dialuric  acid,  uramilic  acid,  and  xanthic  oxide.  They  closed  their 
work  with  a  study  of  murexid,  which  Prout  had  first  prepared 
and  named  ammonium  purpurate.  The  results  of  their  work 
appeared  in  1838.^ 

1  C.  Jobst.  Thein  identisch  mit  Caffein.    Liebig's  Ann.  der  Chem.  u.  Pharm.,  25, 63  (1838). 

2  Giornale  di  Fisica,  Chimica,  etc.,  di  Brugnatelli,  11,  38,  and  117.  Osservazioni  sopra 
varj  cangiamenti  che  avvengono  nell'  ossiurico  (ac  urico)  trattato  coll'  ossisettonoso  (ac 
nitroso) . 

3F.  Wohler.  Poggendorf's  Annalen  der  Physik  und  Chemie,  15,  619  (1829).  Ueber 
die  Zersetzung  des  Harnstoffs  und  der  Harnsiiure  durch  hohere  Temperatur. 

^  Serullas.  Doppelt.  Chlorcyan,  eine  neue  Verbindung  des  Chlors  mit  Cyan,  und  Cyan- 
saure.     Poggendorf's  Annal.,  15,  443  (1828). 

•''  Fourcroy  und  Vauquelin.  Neue  Erfahrungen  iiber  den  Harnstoff.  Journal  fiir  die 
Chemie  Physik  und  der  Mineralogie,  6,  409  (1808). 

•5  J.  Liebig.     Analyse  der  Harnsaure.     Liebig's  Ann.  der  Chem.  u.  Pharm. ,U0,  47  (1834). 

^  Mitscherlich.  Analysen  kohlenstoffhaltiger  Verbindungen.  Poggendorf's  Annal.  d. 
Physik  und  Chemie,  33,  331  (1834). 

8  Buniva  und  Vauquelin.  Ann.  de  Chimie,  33,  269  (1799).  Sur  I'eau  de  I'amnios  de 
femme  et  de  vache. 

9  F.  Wohler  und  J.  Liebig.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  26,  241  (1838).  Unter- 
suchungen  iiber  die  Natur  der  Harnsaure. 


4        The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

From  Liebig  to  Emil  Fischer.  —  During  the  next  twenty-five 
years  we  have  the  work  of  Schlieper  ^  on  hydiirilic  acid  and  dilit- 
uric  acid,  that  of  Wosresensky,^  who  discovered  theobromin;  of 
linger  ^  who  discovered  guanin,  which  had  previously  been 
thought  identical  with  xanthin;  of  Rochleder,  who  studied  caf- 
fein*  and  theobromin,^  and  some  of  their  derivatives;  of  Strecker, 
who  discovered  the  change  of  guanin  to  xanthin  by  the  action  of 
nitrous  acid  ®  and  the  relations  between  guanin,  xanthin,  theo- 
bromin, caffein,  and  creatinin. 

Strecker '  was  the  first  to  change  theobromin  to  caffein  by  the 
action  of  HI  on  the  silver  salt  of  theobromin.  He  obtained 
caffeidin  by  the  action  of  barium  hydroxide  on  caffein.^  He 
studied  the  action  of  sodium  amalgam  on  allantoin  ^  and  the 
decomposition  of  uric  acid  into  carbon  dioxide,  ammonia,  and 
gl3^cocoll,^''  a  decomposition  which  gave  Horbaczewski  a  hint  to  the 
first  synthesis  of  uric  acid. 

In  1843,  Stenhouse  "  studied  the  thein  from  tea.  In  1851, 
Stadeler  studied  uroxamic  acid  and  uroxil.  The  work  of  Unger  ^^ 
in  1845  on  xanthin  and  some  of  its  compounds,  and  that  of  Scherer^^ 
on  the  guanin,  hypoxanthin,  and  xanthin  in  horse  flesh  and  the 
pancreas  conclude  the  important  work  up  to  the  time  of  Bseyer. 

Baeyer's  work  gave  the  first  clew  to  the  constitution  of  many 
members  of  the  uric  acid  group.     He  studied  pseudouric  acid, 

1  Schlieper.  Ueber  Alloxan,  AUoxursaure,  und  einige  neue  Zersetzungsprodukte  der 
Harnsaure.     Liebig's  Ann.  der  Chem.  u.  Pharm.  55,  251  (1845). 

2  A.  Wosresensky.  Ueber  das  Theobromin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  41, 
125  (1842). 

^  Unger.  Bemerkungen  zu  der  Notiz  von  Einbrodt  iiber  die  Zusam.mensetzung  des 
Harnoxyds.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  58,  19  (1846). 

■*  Rochleder.     Ueber  das  Caffein.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  71,  1  (1849). 

5  Ibid.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  79,  124  (1851).  Die  Oxydationsprodukt 
des  Theobromins,  nnd  iiber  die  Zusammensetzung  der  Rubiaceen. 

8  Strecker.  Ueber  der  Verwandlung  des  Guanins  in  Xanthin.  Liebig's  Ann.  der  Chem. 
u.  Pharm.,  108,  141  (1858). 

^  Ihid.  Untersuchungen  iiber  die  chemischen  Beziehungen  zwischen  Guanin,  Xanthin, 
Theobromin,  Caffein,  und  Kreatinin.    Liebig's  Ann.  der  Chem.  u.  Pharm.,  118,  151  (1861). 

8  Ibid.  Ueber  die  Zersetzung  des  Caffeins  durch  Barythydrat.  liebig's  Ann.  der 
Chem.  u.  Pharm.,  123,  360  (1862). 

'  Ibid.  Ueber  einige  Reduktionsprodukte  des  Allantoins  und  der  Harnsaure.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  131,  119  (1864). 

'"  Ibid.  Bildung  von  Glycocoll  aus  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
146,  142  (1868). 

"  J.  Stenhouse.  Ueber  Thein  und  seine  Darstellung.  Liebig's  Ann.  der  Chem.  u. 
Pharm.,  45,  366  (1843),  und  NachtragUches  uber  das  Thein.  Liebig's  Ann.,  46,  227 
(1843). 

12  Unger.     Ueber  das  Xanthin.     Liebig's  Ann.,  65,  222  (1845). 

13  Scherer.  Ueber  Hypoxanthin,  Xanthin,  und  Guanin  im  Thierkorper  und  das  Reich- 
thum  der  Pancreas-driise  an  Leucin.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  112,  257  (1859). 


Chemistry  .  5 

hydurilic  acid  and  its  salts/  violuric  acid,  dilituric  acid  and 
their  salts,  violantin,  and  alloxanbromid.^  He  made  a  special 
study  of  the  alloxan  derivatives,^  and  of  nitromalonic  acid,  meso- 
oxalic  acid,  and  some  of  their  derivatives.* 

Other  articles  of  about  this  time  deserving  mention  are  the 
works  of  Rosengarten  and  Strecker  on  the  action  of  barium 
hydroxide  on  caffeidin^;  that  of  Hill  on  methyl  uric  acid^;  of 
Phillips  ^  on  derivatives  of  caffein  and  theobromin;  Mulder's  work 
on  the  synthesis  of  barbituric  acid  and  other  ureides  ^;  that  of 
Dry  gin  on  ethyl  derivatives  of  uric  acid  ^;  of  Grimaux  ^°  on  uric 
acid  derivatives,  and  of  Hill  and  Mabery  "  on  the  ethers  of  uric 
acid.  Most  important,  perhaps,  of  all  is  the  article  of  Medicus  ^^ 
on  the  constitution  of  the  purin  bodies.  He  proposed  for  uric 
acid  and  some  of  its  derivatives  the  formulae  which  Emil  Fischer 
afterward  proved  to  be  correct. 

STRUCTURE  AND  SYNTHESIS  OF  THE  PURINS 

Structure.  —  Horbaczewski  first  synthesized  uric  acid  by 
melting  together  glycocoU  and  urea,^^  and  later  by  melting  to- 
gether urea  and  the  amide  of  trichlorlactic  acid.'*  Behrend  and 
Roosen  '^  synthesized  it  from  acetoacetic  acid  and  urea.  They 
first  obtained  methyl  uracil,  then  isobarbituric  acid,  and  finally 

1  A.  Baeyer.  Untersuchungen  iiber  die  Harnsauregruppe.  Liebig's  Ann.  der  Chem. 
u.  Pharm.,  127,  1  (1863). 

2/6id.,  127,  199  (1863). 

^Ibid.,  13U,  129  (1864). 

^Ibid.,  131,  291  (1864). 

■''  F.  Rosengarten  und  A.  Strecker.  Ueber  die  Spaltung  des  Caffeidins  durch  Barythy- 
drat.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  157,  1  (1871). 

8  H.  Hill.  Ueber  die  Aether  der  Harnsaure.  Ber.  der  Dtsch.  chem.  GeselL,  9,  370 
(1876). 

'  L.  Phillips.  Notiz  ijber  eine  dem  Caffein  homologe  Base.  Ber.  der  Dtsch.  chem. 
GeselL,  9,   1308  (1876). 

'  Mulder.  Beitrag  zur  Kenntniss  der  Ureide.  Synthese  von  Dimethylbarbitursaure. 
Ber.  der  Dtsch.  chem.  GeselL,  12,  465  (1879). 

9  Drygin.  Jahresber.  fur  Chem.,  1864,  629.  And  Russ.  Zeitschr.  fur  Pharm.  Ill,  3,  49. 
113,  121. 

^°  E.  Grimaux.  Recherches  synthetiques  sur  le  groupe  urique.  Comptes  rendus,  81, 
325  (1875). 

"  H.  Hill  and  C.  Mabery.  On  the  Ethers  of  Uric  Acid.  American  Chem.  Journ.,  2,  305 
(1880). 

'2  Medicus.  Zur  Constitution  der  Harnsauregruppe.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
175,  230   (1875). 

•3  J.  Horbaczewski.     Synthese  der  Harnsaure.     Monatshefte  fiir  Chemie,  3,  796  (1882). 

1'*  Ihid.  Ueber  kiinstUche  Harnsaure  und  Methylharnsaure.  Monatshefte  fiir  Chemie, 
6,  356  (1885). 

^5  R.  Behrend  und  O.  Roosen.  Synthese  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u. 
Pharm.,  251,  235  (1889). 


6         The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

isodialuric  acid.  The  latter  combines  with  urea  to  form  uric  acid. 
The  simplest  method  of  synthesis,  that  of  Fischer  and  Ach,^ 
consists  in  withdrawing  the  elements  of  water  from  pseudouric 
acid  with  oxalic  acid,  or  more  easily  with  boiling  concentrated 
hydrochloric  acid. 

In  1875  Medicus  ^  proposed  the  formula 

NH  — CO 

CO      C  —  NH  X 

I        II  )co 

NH  — C  — NH/ 
for  uric  acid,  and  in  1877  Fittig  ^  proposed  the  formula 

NH  —  C  —   NH 

I         /  I 

CO    CO  I  CO 

I  \       I 

NH  —   C  —   NH 

Emil  Fischer,  in  1882,*  showed  that  the  Medicus  formula  was 
probably  the  correct  one,  at  any  rate,  that  the  Fittig  formula 
could  not  be  correct,  since  there  exist  two  isomeric  monomethyl 
uric  acids.  This,  together  with  other  evidence,  showed  Medicus' 
formula  to  be  correct. 

The  formula  proposed  by  Medicus  agrees  well  with  the  chemical 
behavior  of  uric  acid.  From  it  we  can  understand  the  change  to 
alloxan  and  urea  and  to  carbon  dioxide,  ammonia,  and  glycocoll, 
the  change  to  tetramethyl  uric  acid  by  the  action  of  alkali  and 
methyl  iodide  and  finally  the  existence  of  isomeric  mono-,  di-,  and 
tetramethyl  uric  acids. 

The  tautomeric  formula 

N  =  COH 
COH    C  — NH\ 

II  II  ;coH 

N  —   C  —  N  / 
explains  the  acid  properties  and  many  of  the  reactions  of  uric  acid. 

1  E.  Fischer  und  L.  Ach.  Neue  Synthese  der  Harnsaure  und  ihre  Methylderivate.  Ber. 
der  Dtsch.  chem.  Gesell.,  28,  2473  (1895). 

2  Medicus.  Zur  Konstitution  der  Harnsauregruppe.  Liebig's  Ann.  der  Chem.  u. 
Pharm.,  175,  230  (1875). 

3  R.  Fittig.  Wohler's  Grvmdriss  der  organischen  Chemie.  lOt  Aufl.,  Leipzig,  1877, 
p.  309. 

■*  E.  Fischer.  Umwandlung  von  Xanthin  in  Theobrorain  und  Caffein.  Ber.  der  Dtsch. 
chem.  Gesell.,  15,  395  (1882). 


Chemistry  7 

Both  of  these  compounds  may  exist.  It  is  impossible  by  our 
present  methods  to  distinguish  between  these  two  formulse,  the 
lactam  and  the  lactim.  This  same  difficulty  has  appeared  in 
determining  the  constitution  of  other  bodies;  for  example,  aceto- 
acetic  acid,  which  sometimes  appears  to  have  the  formula  CH3- 
COCH2COOH  and  sometimes  CH3COHCHCOOH.  We  know 
that  the  amorphous  uric  acid  set  free  in  the  cold  from  salts  has 
different  properties  from  the  crystalline  uric  acid  obtained  by 
boiling  or  on  long  standing.  In  the  case  of  the  alkyl  derivatives 
we  can.  of  course,  easily  tell  whether  or  not  the  alkyl  group  is 
attached  to  nitrogen  or  oxygen.  We  have,  in  fact,  derivatives 
of  both  the  lactam  and  the  lactim  formula.  Wislicenus  and 
Koerber  *  in  changing  methoxycaffein 
CH3N  — CO 

CO   C  — NCHjv 

I        II  >C0CH3 

CH3N  — C    —    N   ^ 

into  tetramethyluric  acid 

CH3N  — CO 

CO  C  — NCHgv 

I     II  ^co 

CH3N  — C  — NCH3/ 

by  heating  have  given  us  an  example  of  change  of  one  form  into 
the  other. 

The  C5H4  or,  structurally, 

_N— C  = 
I        I  / 

=c     c— n( 

I         II  \p 

I      II         /^ 

— N— C— n/ 

group  is  called  the  purin  nucleus  by  Emil  Fischer,  and  all  the 

purin  bodies  have  both  the  meta-diazine  and  the  imidazole  rings. 

Wallach^  and  Rung  and  Behrend^  first  showed  that  imidazol 

(a)HC  — NH(r;)\ 

II  ^CH(;.) 

(/?)HC     —     N  ^ 

1  V/islicenus  und  H.  Koerber.     Ueber  die  Umlagerung  von  Laktimathem  in  Laktame. 
Ber.  der  Dtsch.  chem.  Gesell.,  35,  1991  (1902). 

2  Wallach.     Ueber  das  Verhalten  einige  Diazo-  und  Diazoaminoverbindungen.     Liebig's 
Ann.  der  Chem.  u.  Pharm.,  235,  233  (1886). 

5  Rung  und  Behrend.     Notizen  iiber  Glyoxalin.     Liebig's  Ann.  der  Chem.  u.  Pharm., 
271,  28  (1892). 


8        The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

will  react  with  diazo-bodies  to  form  diazoamino  compounds. 
They  showed  that  imidazol  will  react  with  diazobenzolchlorid  to 
form  T?-diazobenzolimidazol.  Burian  ^  showed  that  the  a,  ^,  and 
;*  substitution  products  can  also  be  diazotized,  and  that  the  action 
fails  only  when  the  hydrogen  atom  in  position  (r/)  is  already  sub- 
stituted. This  author  showed  that  purin  bodies  like  xanthin, 
hypoxanthin,  guanin,  adenin,  and  theophyllin  (1,  3,  dimethylxan- 
thin),  in  which  the  hydrogen  atom  in  position  (7)  is  not  substi- 
tuted, can  be  made  to  form  diazoamino  compounds  in  the  same 
way.  In  such  compounds  as  caffein,  1,  3,  7,  trimethylxanthin, 
and  itheobromin,  3,  7,  dimethylxanthin,  where  the  hydrogen 
atom  in  position  (7)  is  substituted,  no  diazo  derivative  can  be 
found.  This  is  important  as  it  gives  us  a  method  of  finding 
how  the  purin  bodies  are  combined  in  nucleic  acids. 

The  Germans  follow  Fischer  and  number  the  atoms  as  follows: 

(1)N-(6)C 

(2)C       (5)C-N(7)v 

I  I  )C(8) 

(3)N— (4)C  — N(9)/ 

Some  of  the  English  follow  a  slightly  different  numbering. 

We  have  the  choice  of  two  tautomeric  formulae  for  purin,  viz.: 

N  =  CH  N  — CH 

CH      C  —  N  -^  or      CH   C  — NH\ 

II  II  ;CH  II        II  )CH 

N  —  C  — NH/  N  — C  — NH^ 

This  tautomerism  is  observed  in  all  derivatives  of  purin  in  which 
there  is  no  oxygen  in  the  imidazole  ring,  therefore  in  xanthin, 
hypoxanthin,  adenin,  theophyllin,  etc.,  Emil  Fischer  has  obtained 
in  several  cases  both  isomeric  methyl  products,  where  only  one 
hydrogen  compound  exists. 

Theoretically,  three  monoxypurins  are  possible,  I,  II,  and  III. 
N  =  CH  NH  — CO  N   =  CH 

NH\  CH      C  — NH\ 

;cH      II       II  ;co 

-.N  ^  N  —  C  — NH/ 

III 

We  can,  of  course,  imagine  the  corresponding  lactim  formulae 

1  R.  Burian.  Diazoaminoverbindungen  der  Imidazole  iind  der  Purinsubstanzen.  Ber. 
der  Dtsch.  chem.  GeselL,  37,  696  (1904). 


CO 
NH- 

C- 

-C  - 

I 

-NH\ 

)CH 

CH 

II 

-      N  - 

C- 

II 
-  C 

II 

Chemistry  9 

instead  of  the  formulie  given.     Formula!  II  and  III  themselves 

and  methyl  derivatives  are  all  three  known.  Similarly,  there  arc 
three  monoamine  purins. 


N  =  CH 

N  =  CNH2 

N  = 
1 

=  CH 

CNH,  C  — NH\ 

II        "II              >NH 
N  —   C  —  N^ 

CH    C  — NH\ 

II     II        ;cH 

N  — C  —  N^ 

1 
CH 

N  — 

C  — NH\ 

II                ;  CNH. 

.  C-N^          ' 

IV 

V 

VI 

NH- 

-CO 

N  = 

:  CH 

NH- 

-CO 

CO 
NH- 

C  — NH\ 

II               /CH 
-C  —  N-^ 

CO 
NH- 

C  — NH\ 

II               /CO 
-C  — NH/ 

CH 

II 

N  — 

C  — NH 

II 

C  — NH 

VII 

VIII 

IX 

V  is  adenin.     Methyl  derivatives  of  all  three  are  known. 
Three  isomeric  dioxypurins  are  likewise   possible,  VII,  -VIII, 
and  IX. 


;C0 


VII,  which  is  xanthin,  and  IX,  and  methyl  derivatives  of  all 
three,  have  been  prepared. 

Synthetical  Methods.  —  Five  methods  have  been  of  especially 
great  service  in  the  synthesis  of  the  members  of  the  uric  acid 
group  by  Fischer.^ 

1.  The  preparation  of  uric  acid  and  its  methyl  derivatives  from 
pseudouric  acid. 

2.  The  methylating  of  uric  acid  and  xanthin. 

3.  The  change  of  uric  acid  and  dioxypurin  to  chlor  derivatives 
by  the  use  of  PClg. 

4.  The  change  from  the  chlor  derivatives  to  the  oxy,  thio,  and 
amino  derivatives. 

5.  The  reduction  of  the  chlor  purins  with  zinc  dust  or  hydriodic 
acid. 

Synthesis  of  Uric  Acid  from  Pseudouric  Acid.  — 


+        H„0 
,C0 


1  E.  Fischer.     Synthese  in  der  Puringruppe.     Ber.  der  Dtscb.  chein.  Gesell.,  32,  435 
(1899). 


NH  — CO 

NH  — CO 

1           1 

CO      CH  — NH  — CO- 

1           1 

-NH^ 

CO       C  — NH 

1           II 

NH  — C— NH 

NH  — CO 

pseudouric  acid 

uric  acid 

10       The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

This  dehydration  was  first  brought  about  by  melting  pseudouric 
acid  with  oxalic  acid.^  Later,  the  simple  method  of  boiling  with 
hydrochloric  acid  was  used.^  This  is  only  one  of  the  many 
examples  of  synthesis  by  this  method.  It  serves  as  a  support  for 
the  formula  we  now  hold  for  uric  acid. 

The  Alkylating  of  the  Oxypurins.  —  Hill  and  Mabery  ^  first 
prepared  methyl  and  dimethyl  uric  acid  by  heating  lead  urate 
with  methyl  iodide  in  a  closed  tube  at  160°.  Fischer's  method  of 
preparing  methyl  derivatives  consists  in  shaking  a  solution  of 
alkaline  urate  with  warm  methyl  iodide.  This  method  can  be 
used  with  all  oxypurins  and  their  derivatives  except  the  halogen 
derivatives.^  The  latter  react  with  more  difficulty.  Strecker  ^ 
was  the  first  to  prepare  a  methyl  xanthin. 

Preparation  of  the  Chlor  Purins.  —  E.  Fischer  first  prepared 
chlor  derivatives  of  purin  by  heating  methyl  uric  acid 

NH— CO 

CO      C  — NH\ 

I  II  /CO 

NH  — C  —  N\ 

\CH3 

with    phosphorus  oxy-chloride  and  phosphorus  pentachloride  to 
130°.     He  obtained  9-methy  1-8- oxy-2-6-di-chlor-purin. 


N  = 

=  CC1 

1 

CCl 

N  — 

1 
C  — 

II 

C  - 

NH\ 

/CO 
-  N< 

^CH, 

3r  heating 

gave 

9-me 

thyl- 

■tri-chlor-purin. 

N  = 
1 

=  CC1 
1 

CCl 

N  - 

1 
C- 

-  c- 

/CCl 

-n( 

\CH, 

1  E.  Fischer  und  L.  Ach.     Neue   Synthese  der  Harnsaure  und   ihrer   Methylderivate. 
Ber.  der  Dtsch.  chem.  Gesell.,  28,  2473  (1895). 

2  E.  Fischer.     Neue  Synthese  der  Harnsaure,  des  Hydroxycaffeins  und  des  Aminodioxy- 
purines.     Ber.  der  Dtsch.  chem.  Gesell.,  30,  559  (1897). 

3  H.  Hill  and  C.  Mabery.     On  the  Ethers  of  Uric  Acid.     American  Chem.  Journ.,  2,  305 
(1880). 

H.  Hill.     Ueber  die  ^Ether  der  Harnsaure.     Ber.  der  Dtsch.  chem.  Gesell.,  9,  370  (1876). 
*  A.  Strecker.    Untersuchungen  iiber  die  chemischen  Beziehungen  zwischen  Guanin,  Xan- 
thin, Theobromin,  Caffein,  und  Kreatinin.    Liebig's  Ann.  d.  Chem.  u.  Pharm.,  118, 151  (1861). 


Chemistry  1 1 

In  obtaining  chlorine  derivatives  in  many  of  the  group,  the 
results  depend  in  great  measure  on  the  temperature  and  the  sub- 
stituted radicles  in  the  compound.^ 

Change  of  the  Halogen  Purins  into  Oxy-  Thio-  and  Amino-Purins. 
—  The  replacement  of  halogen  by  hydroxyl  can  be  often  brought 
about  by  aqueous  alkali.^  This  method  does  not  always  work, 
however.^  The  output  of  hydroxycaffein,  for  example,  by  the 
action  of  aqueous  alkaU  on  chlor-  or  brom-caffein  is  small.*  Much 
better  results  are  obtained  by  the  action  of  alcoholic  alkali. 
Hydroxy  caff  ein  can  be  obtained  in  this  way  from  chlor-  or  brom- 
caffein.^ 

Chlorine  can  be  replaced  by  hydroxyl  in  almost  all  cases  by 
the  action  of  hydrochloric  acid  at  125°-130°  C.*-'' 

The  derivatives  are  prepared  from  the  halogen  derivatives 
by  the  action  of  KSH.     For  example,  trichlorpurin 

N  =  CCl 

I  I 

CCl      C  — NH\ 

II  II  ^cci 

N  —  C  —  N  -^ 
is  changed  to  tri-thio-purin 

N  =  CSH 

CSH    C  — NH\ 

II  II  >CSH 

N  —  C—  N  ^ 

by  excess  of  KSH  at  100°.^ 

1  E.  Fischer.     Ueber  die  Harnsaure.     Ber.  der  Dtsch.  chem.  Gesell.,  17,  328  (1884). 
Ibid.     Verwandlung  des  Theobromins  in  methylirte  Hamsauren.    Ber.  der  Dtsch.  chem. 

Gesell..  28,  2480  (1895). 

Ibid.      Ueber  die  Tetramethylhamsaure.     Ber.  der  Dtsch.  chem.  Gesell.,  30,  3010  (1897) . 

E.  P^ischer  und  L.  Ach.  Ueber  das  Oxydichlorpurin.  Ber.  der  Dtsch.  chem.  Gesell., 
30,  2208  (1897). 

2  E.  Fischer.  Ueber  die  beiden  Methyltrichlorp urine.  Ber.  der  Dtsch.  chem.  Gesell., 
30,  1846  (1897). 

3  E.  Fischer  und  L.  Ach.  Ueber  die  1-9  Dimethylharnsaure  und  die  1-7-9  Trimethyl- 
harnsaure.     Ber.  der  Dtsch.  chem.  Gesell.,  32,  250  (1899). 

*  E.  Fischer.  Verwandlung  des  Theobromins  in  methylirte  Hamsauren.  Ber.  der 
Dtsch.  chem.  Ge.sell.,  28,  2480  (1895). 

5  Ibid.  Ueber  Caffein,  Theobromin,  Xanthin,  und  Guanin.  Liebig's  Ann.  der  Chem. 
u.  Pharm.,  216,  253  (1882). 

*  E.  Fischer  und  L.  Ach.  Ueber  das  Oxydichlorpurin.  Ber.  der  Dtsch.  chem.  Gesell., 
30,  2208  (1897). 

E.  Fischer.  Ueber  die  Tetramethylhamsaure.  Ber.  der  Dtsch.  chem.  Gesell.,  30,  3009 
(1897). 

E.  Fischer  und  L.  Ach.  Ueber  die  1-9  Dimethylharnsaure  und  die  1-7-9  Trimethyl- 
harnsam-e.     Ber.  der  Dtsch.  chem.  Gesell.,  32,  250  (1S99). 

'E.  Fischer.     Ueber  Thiopurine.     Ber.  der  Dtsch.  chem.  Gesell.,  31,  431  (1898). 


12      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Ammonia,  alcoholic  ammonia,  and  aqueous  ammonia  act  on 
the  chlor-purins  and  give  amino  derivatives.  By  the  action  of 
nitrous  acid  on  the  amino  derivatives  we  can  again  obtain  the 
oxypurins. 

The  Reduction  of  the  Halogen  Derivatives.  —  The  halogen  de- 
rivatives can  be  reduced  to  the  hydrogen  compounds  by  the 
action  of  HI  or  of  phosphonium  iodide.^  In  the  case  of  the  chlor- 
purins  which  do  not  contain  oxygen,  the  action  is  more  difficult.^ 
If,  however,  we  carry  on  the  reaction  at  0°  C,  iodo-purins  are 
formed,  and  these  can  be  reduced  to  the  purins  by  the  action  of 
zinc  dust  and  water.^    Thus  hydriodic  acid  changes  trichlorpurin 

N  =  CCl 

I  I 

CCl      C  — NH\ 

II  II  )cci      , 

N  —  C—  N  ^ 
to  di-iodo  purin 

N  =  CI 

I  I 

CI       C— NH\ 

II  II  )CH 

N  —  C  —  N    ^ 

N  =  CH 

I  I 

CH      C— NH\ 

II  II  )CH 
N  —  C—  N  ^ 

is  obtained  from  the  latter  by  the  action  of  zinc  dust  and  water. 

The  Special  Chemistry  of  the  Important  Purin  Bodies  and  of  the 

Monoureides 

TRIOXYPURIN    (URIC   ACID)  AND    DERIVATIVES 

Occurrence  of  Uric  Acid.  —  Uric  acid  has  been  found  in 
the  urine  of  the  elephant  by  Horbaczewski,*  in  the  urine  of  swine 

1  E.  Fischer.     Ueber  die  Harnsaure.     Ber.  der  Dtseh.  chem.  Gesell.,  17,  332  (1884). 

''Ibid.     Ueber  Hydurinphosphorsaure.     Ber.  der  Dtsch.  chem.  Gesell.,  31,  2546  (1898). 

3  Ibid.  Ueber  das  Purin  und  seine  Methylderivate.  Ber.  der  Dtsch.  chem.  Gesell., 
31,  2550  (1898). 

■*  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xan- 
thinbasen,  sowie  der  Entstehung  der  Leucocytosen  im  Saugethierorganismus.  Monat- 
shefte  fur  Chemie,   12,  221   (1891). 


at  0°,  and  purin 


Chemistry  13 

by  Meissl  and  Strohmer,^  Salomon,^  and  Mittelbach,^  in  camel's 
urine  by  Brand, ^  in  horse's  urine  by  Salkowski,^  and  Le  Conte,* 
in  cow's  urine  by  Briicke  ^  and  Meissner  and  Shepard.*  Mittelbach 
found  it  in  the  urine  of  all  the  herbivora  that  he  studied,  but  not 
always  in  the  urine  of  carnivora.  It  is  often  lacking  in  the  urine  of 
dogs  and  cats.  According  to  Meissner,''  it  is  found  regularly  only 
when  they  live  on  animal  food  or  starve,  and  disappears  when  they 
live  on  food  poor  in  proteid.  Mills  ^^  found  uric  acid,  but  no  urea, 
in  the  urine  of  the  tortoise.  Garrod  "  states  that  with  the  exception 
of  the  class  of  arachnids,  scorpions  and  spiders  for  example,  which 
excrete  guanin,  all  the  invertebrates  excrete  uric  acid. 

It  was  found  in  bladder  stones  and  human  urine  by  Scheele,'^ 
in  gouty  concretions  by  Pearson/^  by  Fourcroy  and  Vauquelin  " 
in  birds'  excrement,  and  in  serpent  excrement  by  Prout.^-^  It 
was  not  found  in  the  urine  of  the  carp,  frogs,  or  sharks  by 
Schreiber.^^  It  was  found  in  the  green  glands  of  the  crab  by 
Griffiths ,^^  and  in  the  malpighian  vessels  of  periplaneta  orientalis 

'  E.  Meissl  und  F.  Strohmer.  Ueber  die  Bildung  von  Fett  aus  Kohlenhydraten  im 
Thierkorper.     Monatshefte  fiir  Chemie,  4,  801  (1883). 

^G.  Salomon.  Ueber  die  chemische  Zusammensetzung  des  Schweinharn.  Du  Bois 
Arch,  fiir  Physiol.,  8,  175  (1S84). 

3  F.  Mittelbach.  Ueber  das  Vorkommen  der  Harnsaure  im  Harne  der  Herbivoren. 
Zeitschr.  fiir  physiol.  Chem.,  12,  465  (1888). 

*  G.  Meissner.  Ueber  die  Ausscheidung  von  Kreatin,  Kreatinin,  und  einiger  anderen 
stickstoffhaltigenUmsatzprodukten  bei  Saugethieren.  Zeitschr.  fur  ration.  Med.  (3),  31, 
283  (1868). 

5  E.  Salkowski.  Ziu-  Kenntniss  des  Pferdeharns.  Zeitschr.  f.  physiol.  Chem.,  9,  241 
(1885). 

6  Bernard.     Legons  sur  les  liquides  de  I'organisme,  2,  59. 

'  E.  Briicke.     Harnsaure  im  Rindsharn.     Jour,  fur  prakt.  Chem.,  25,  254  (1842). 

Ibid.     Vorkommen  von  Harnsaure  im  Rinderharn.     Miiller's  Arch.,  1842,  91. 

8  Meissner  und  Shepard.  Untersuchungen  iiber  das  Entstehung  der  Hippursaure  im 
Thierorganism,  81  (1866). 

'  G.  Meissner.  Ueber  das  Entstehen  der  Bernsteinsaure.  Zeitschr.  fur  ration.  Med. 
(3),  24,  97  (1865). 

1"  T.  Mills.  Notes  on  the  Urine  of  the  Tortoise,  with  Special  Reference  to  Uric  Acid  and 
Urea.     Journ.  of  Physiol.,  7,  453  (1886). 

"  A.  Garrod.  Uric  Acid:  Its  Physiology,  and  Its  Relation  to  Renal  Calculi  and  Gravel. 
Brit.  Med.  Journ.,  495,  547,  601,  651,  704,  and  751  (1883),  I. 

12  K.  W.  Scheele.  Examen  chemicum  Calculi  urinarii.  Opuscular,  II,  73.  Also,  Lorenz 
Crell.     Die  neuesten  Entdeckungen  in  der  Chemie,  III,  227. 

13  Pearson.     Philosophical  Transactions  of  the  Royal  Society,  London,  1798,  15. 

w  Fourcroy  et  Vauquelin.  Sur  le  guano  ou  sur  I'engrais  naturel  des  ilots  de  la  mer  du 
Sud  pres  des  cotes  du  Perou.     Annales  de  Chimie,  56,  258  (1805). 

15  Thomson.  Analysis  of  the  Excrements  of  the  Boa  Constrictor.  Annals  of  Philosophy, 
5,  413. 

16  Schreiber.  Ueber  die  Harnsaure  unter  physiologischen  und  pathologischen  Beding- 
uugen,  1899,  25.     Stuttgart. 

1^  A.  Griffiths.  On  the  Extraction  of  Uric  Acid  Crystals  from  the  Green  Gland  of  Astacus 
Fluviatilis.     Chem.  News,  51,  121  (1885). 


14     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

by  MacMunn.^  Hopkins  ^  found  that  the  white  pigment  which  hes 
between  the  two  chitin  layers  of  the  scales  of  the  pierida  brassica 
is  uric  acid.  Krukenberg  ^  found  uric  acid  in  almost  all  the 
organs  of  lampyris  splendidula,  an  invertebrate.  Davy  *  found 
uric  acid  in  the  blood  of  invertebrates. 

Synthesis  of  Uric  Acid.  - —  A  study  of  the  various  syntheses 
of  uric  acid  is  of  importance  from  a  physiological  standpoint, 
isince,  if  uric  acid  is  synthesized  in  the  body,  as  some  writers  main- 
tain, the  synthesis  may  take  place  in  a  manner  similar  to  one  of 
the  artificial  methods. 

Horbaczewski  ^  was  the  first  to  synthesize  uric  acid.  He  gave 
two  methods.  The  first  consisted  of  fusing  together  glycocoll 
and  urea,  the  second  in  fusing  together  the  amide  of  trichloracetic 
acid  and  urea.  The  output  in  each  case  was  small,  and  the 
methods  have  not  been  of  general  use  in  the  synthesis  of  other 
members  of  the  group. 

Behrend  and  Roosen,^  in  1888,  synthesized  uric  acid  from 
aceto-acetic  acid  and  urea.  The  changes  are  shown  below 
graphically: 


COOC2H5 

COCH3 
I 

aceto-acetic  ether 


NH  —  CO  NH  —  CO  NH  —  CO 

CO  CH  CO  C  — NO,  CO        C  — NO2 

C  — COOH  NH— CH 
III  IV 


NH  —  CCH3       NH 
II 


methyl  uracil 


nitrouracUic  acid 


nitrouracil 


NH  —  CO  NH  —  CO 

CO         C  — NH,    CO  COH 


NH  —  CH 
V 

amidouracil 


NH  —   CH 
VI 

oxyuracil 


NH 

CO 

I 
NH 


CO 
COH 


NH  —CO 

I  I 

CO        C  — NH- 


;C0 


COH         NH— C  — NH/ 
VII  VIII 

isodialuric  acid  uric  acid 


1  C.  MacMunn.  Note  on  a  Method  of  Obtaining  Uric  Acid  Crystals  from  the  Malpighian 
Tubes  of  Insects  and  from  the  Nephridium  of  Pulmonate  Molusca.  Journ.  of  Physiol., 
7,   128  (1886). 

2  F.  Hopkins.  The  Pigments  of  the  Pieridse :  A  Contribution  to  the  Study  of  Excretory 
Substances  which  Function  in  Ornament.     Phil.  Trans.,  London,  186,  661  (1895). 

3  Krukenberg.     Vergl.  Physiol.  Studien  an  den  Kiisten  der  Adria,  II.     Abtheil,  29. 

*  A.  Garrod.     Uric  Acid :   Its  Pathology  and  its  Relation  to  Renal  Calculi  and  Gravel. 
Brit.  Med.  Journ.,  1883,  I,  495,  547,  601,  651,  704,  and  751. 
""''  ijLJ^Jorbitczewski.     Synthese  der  Harnsaure.     Monatshefte  fiir  Chemie,  3,  796  (1882). 
8  R.  Behrend  und  O.  Roosen.     Synthese  der  Harnsaure.     Liebig's  Ann.  der  Chem.  u. 
Pharm.,  251,  235  (1889). 


Chemistry  15 

/?-ethyl-uramidocrotonic  acid  is  obtained  by  heating  together 
aceto-acetic  acid  (I)  and  urea.  This,  on  treatment  with  KOH, 
gives  methyl  uracil  (II).  Concentrated  nitric  acid  changes 
methyl  uracil  (II)  to  nitrouracilic  acid  (III),  whose  potassium 
salt  on  boiling  gives  nitrouracil  (IV).  Zinc  and  HCl  reduce 
nitrouracil  (IV)  to  amidouracil  (V),  and  bromin  changes  amido- 
uracil  (V)  to  oxyuracil  (VI)  and  isodialuric  acid  (VII).  Under 
the  influence  of  sulphuric  acid  isodialuric  (VII)  acid  unites  with 
urea  to  form  uric  acid  (VIII). 

Emil  Fischer  has  given  us  a  good  general  method  for  the  syn- 
thesis of  uric  acid  and  its  derivatives.^  He  treats  pseudouric 
acid  with  oxalic  acid  or  with  hydrochloric  acid.  The  complete 
synthesis  from  urea  and  malonic  acid  is  given  graphically  below: 


NH, 

COOH 

NH  —  CO 

1               1 

NH  —  CO 

1              1 

CO 

1 

CH2 

CO         CH2 

CO          C  =  NOH 

1               1 

NH2 

COOH 

NH   —  CO 

NH  —  CO 

I 

II 

III 

IV 

urea 

malonic  acid 

malonylurea 

oximidomalonylurea 

NH    - 

-  CO 

NH  — 

CO 

NH  — CO 

1           1 

CO 

CH  — 

1 

NH2      CO 

CH 

—  NHCONH2 

CO       C  — NH\ 

1       II    -     )co 

NH  — C  — NH/ 

NH   - 

-  CO 

NH  — 

CO 

V 

VI 

VII 

violuric  acid 

pseud 

ouric  acid 

uric  acid 

Urea  (I)  and  malonic  acid  (II),  when  treated  with  POCI3  give 
malonylurea  (III).  Nitrous  acid  changes  malonylurea  (III)  to 
oximidomalonylurea  (IV).  Potassium  cyanate  (KCNO)  and 
oximidomalonylurea  (IV)  react  to  form  violuric  acid  (V),  which 
unites  with  urea  to  form  pseudouric  acid  (VI).  Pseudouric  acid 
changes  to  uric  acid  on  treatment  with  hydrochloric  or  oxalic 
acid,  which  withdraws  from  the  pseudouric  acid  the  elements  of 
water. 

Traube  ^  succeeded  in  synthesizing  members  of  the  purin  group 
from  cyanacetic  ester  (CNCH.COOCaHg).      This  condenses  with 

1  E.  Fischer  und  L.  Ach.  Neue  Synthese  der  Harnsaure  und  ihrer  Methylderivate.  Ber. 
der  Dtsch.  chem.  Geseli.,  28,  2473  (1895). 

^  W.  Traube.  Ueber  eine  neue  Synthese  des  Guanins  und  Xanthins.  Ber.  der  Dtsch. 
chem.  GeseU.,  33,  1371  (1900). 


16     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

giianidin  NH  :  C(NH2)2  in  alcoholic  solution  to  cyanacetylguan- 
idin  (I),  which,  under  the  influence  of  alkah,  changes 


NH  —  CO 

I  I 

C  :  NH  CH2 

I  I 

NH.,        CN 


(I) 


to  iminomalonylguanidin  or  2-4-diamino-6-oxypyrimidin  (II) 

NH  —  CO 

C:  NH   CH,         (II) 

I  I     ' 

NH  —  C :  NH 

The  iminomalonylguanidin  can  be  changed  to  guanin  by  the 
methods  used  to  change  pyrimidin  derivatives  to  purin  deriva- 
tives.^ The  guanin  can  then  be  changed  to  the  other  members  of 
the  purin  group. 

Another  method  for  the  synthesis  of  members  of  this  group 
is  that  through  the  uracil  derivatives.  Emil  Fischer  ^  has  given 
us  the  first  part  of  the  synthesis,  —  the  preparation  of  uracil 
derivatives,  a  number  of  which  he  prepared  and  described. 
The  uracils  are  prepared  by  union  of  /?-amino  acid  esters  and 
urea  after  withdrawal  of  the  elements  of  water.  Hydrouracil, 
for  example,  is  prepared  from  acrylic  acid  and  urea: 


CH.COOH 
CH^ 

+ 

NH, 

CO           = 

NH, 

CH,  — CO  —  NH 
CH,  — NH  — CO 

acrylic  acid 

urea 

hydrouracil 

+ 


H,0 


The  second  part  of  the  synthesis,  the  preparation  of  purins  from 
uracils,  is  due  to  Gabriel  and  Coleman.^  The  synthesis  of  6-2- 
methyl-amido-purin  from  methyl  uracil  is  an  example  of  their 
method. 

1  S.  Gabriel  vind  J.  Coleman.  Synthesen  in  der  Purinreihe.  Bar.  der  Dtsch.  chem. 
Gesell.,  34,  1234  (1901). 

2  E.  Fischer  und  G.  Roeder.  Synthesedes. Uracils,  Thymins,  und  Phenyluracils.  Ber. 
der  Dtsch.  chem.  Gesell.,  34,  3751  (1901). 

3  Gabriel  und  Coleman.  Synthesen  in  der  Purinreihe.  Ber.  der  Dtsch.  chem.  Gesell., 
34,  1234  (1901). 


Chemistry  17 


NH  — C.CH3 

1           II 

N  —  C.CH3 

II           II 

N   —  CCH3 

1           II 
CO       CH 

CCl      CH 

CNH,  CH 

1        '    1 

NH  — CO 

N  =  CCl 

N  =  C.NH2 

I 

II 

III 

N   —    CCH3 
C.NH2  C.NO2 
N    =   C.NH2 

N    —  CCH, 

II             II 
CNH2   C.NH, 

N    =   CNH^ 

N  =  CCH3 

CNH,  C  — NH\ 

II            II               .CH 
N  —   C  — N    ^ 

IV 

V 

VI 

PCI5  changes  methyl  uracil  (I)  to  di-chlor-methyl-pyrimidin 
(II),  and  this  is  changed  to  4-2-6-diamido-methyl-pyrimidin 
(III)  by  ammonia.  4-2-6-diamido-methyl-pyrimidin  (III)  on 
nitration  with,  concentrated  nitric  acid  changes  to  6-4-2-5-methyl- 
diamido-nitro-pyrimidin  (IV),  which,  on  reduction  with  tin  and 
hydrochloric  acid  gives  6-4-2-5-methyl-tri-amido-pyrimidin  (V). 
Formic  acid  changes  the  latter  to  6-2-methyl-aniido-purin  (VI), 
which  can,  of  course,  be  changed  to  uric  acid  and  other  members 
of  the  group. 

Still  more  recently  Traube  ^  has  offered  a  new  method  of  syn- 
thesizing purin  derivatives  from  derivatives  of  urea  and  the 
monoureides.     In  the  first  method,  thiourea 

NH, 

I 
CS 

I 
NH, 

and  cyanacetic  ester 

COOC2H5 

CH, 

I     ■ 

C  =  N 

are  condensed  to  form  4-amino-6-oxy-2-thio-pyrimidin, 

NH  — CO 

I  I 

CS        CH, 

I  I 

NH  — C  =  NH 

1  W.  Traube.  Der  Aufbau  der  Xanthinbasen  aus  der  Cyanessigsiiure.  Synthese  dea 
Hypoxanthins  und  Adenins.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  331,  64  (1904). 


18     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

or  4-amin.o-2-thio-uracil, 

N  =  COH  NH  — CO 

CSH    CH  or  CS        CH 

II  II  I  II 

N  —  CNH2  NH  — CNH2 

The  methylene  group  of  this  compound  reacts  with  nitrous  acid 
with  spHtting  off  of  HgS  to  form  an  isonitroso  compound  which, 
on  reduction,  gives  4-5-diamino-2-thio-uracil, 

NH  — CO 

I  I 

CS        CNH, 

NH  —  CNH„ 
or  4-5-diamino-6-oxy-2-thio-pyrimidin, 

N  =  COH 

I  I 
CSH    CNH„ 

II  II 

N  —  CNH 

By  heating  the  monoformyl  derivative  of  this  diaminothiouracil 
we  get  6-oxy-2-thio-purin, 

NH  — CO 

I  I 

CS       C  — NH 


iIh  — C  —  N  /" 


CH 


or  2-thiohypoxanthin, 


NH  — CO 

I  I 

CSH     C  — NH\ 

II  II  )CH 

N  —   C  — N  ^ 

Nitric  acid  oxidizes  this  thiohypoxanthin  to  hypoxanthin, 

NH  — CO 

I  I 

CH      C  — NH\ 

i  II  )CH 

N  —  C  —  N  -^ 


Chemistry  19 

In  the  second  method,  thiourea, 

NH, 

I 

CS 
I 

and  malonitril  (methyl  cyanid), 

C  =  N 

I 
CH, 

I 

C  =  N 

are  condensed  to  4-6-diamino-2-thio-pyrimidin, 

NH— C  =  NH 

II 
CS        CH2 

I  I 

NH— C  =  NH 

or  4-6-diamino-2-thio-uracil, 

N  =  CNH2 

I  I 

CSH     CH 

N   —   CNH2 

This  is  easily  changed  to  the  isonitroso  derivative,  and  the  latter 
reduced  to  4-5-6-triamino-2-thio-pyrimidin, 

N  =  CNH2 

I  I 
CSH    CNH2 

II  II 

N  —  CNH, 

If  we  boil  this  with  formic  acid,  and  heat  the  resulting  com- 
pound, we  get  2-thio-adenin,  or  6-amino-2-thio-purin, 

N  =  CNH2 

CSH    C  — NH\ 

II  II  )CH 

N  —  C—  N  ^ 


This  changes  to  adenin, 


N  =  CNHj 

I  I 

CH     C  — NH\ 

II  II  /  CH 
N  —  C—  N^ 


on  treatment  with  hydrogen  peroxide. 


NH^         C2H5OCO 

NH- 

1 

-CO 

1 

CH3SC           +           CH 

1                          il 

=      CH.SCH 

II 

CH 

11 

+      ( 

NH2           NaOCH 

II 

N  - 

II 
-  CH 

NH— CO 

NH- 

1 

-CO 

CH3SC          CH      + 

II           II 

H2O 

'    = 

1 
CO 

CH 

II           II 
N  —    CH 

NH 

-CH 

20      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

A  synthesis  of  thymin  has  been  proposed  by  Wheeler  and 
Merriam.^  Methyl-pseudo-thio-urea  can  be  condensed  with 
the  sodium  salt  of  formyl  acetic  acid  to  form  a  compound  which, 
when  boiled  with  concentrated  HCl,  gives  thymin. 


C,H-,OH      +      NaOH 


+      CH,SH 


Decomposition  and  Oxidation  of  Uric  Acid.  —  Uric  acid 
decomposes  on  heating  ^  into  ammonia  carbonic  acid  and  cyan- 
uric  acid 

N 

/-  \ 
COH     COH 

N  N 

COH 

If  it  is  boiled  with  water  for  fifty  hours  with  exclusion  of  air, 
dialuric  acid 

NH  — CO 

CO      CHOH 

NH  — CO 

and  urea  are  formed.^ 

According  to  Wohler/  heating  at  150°  with  water  changes  it 
to  ammonium  urate.  No  ammonia  is  formed  by  boiling  it  with 
the  urates  ^  or  with  magnesium  ^  for  four  hours.     According  to 

1  Wheeler  and  Merriam.  On  Some  Condensation  Products  of  the  Pseudothioureas : 
Synthesis  of  Uracil,  Thymin,  and  Similar  Combinations.    Am.  Chem.  Journ.,  29,  478  (1903) . 

2  K.  W.  Scheele.  Examen  chemicum  Calculi  urinarii.  Opuscular  II,  73.  Also,  Lorenz 
Crell.     Die  neuesten  Entdeckungen  in  der  Chemie,  III,  227. 

3  M.  Magnier  de  la  Source.  Action  de  I'eau  sur  I'acide  urique.  Bull,  de  la  Soc.  Chim. 
(2),  23,  483  (187.5). 

*  Wohler.  Verfahren  um  Substanzen  mit  Wasser  iiber  100°  zu  erhitzen.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  103,  118  (1857). 

5  Cazeneuve  et  Hugounenq.  Sur  un  nouveau  appareil  pour  le  dosage  precis  de  I'ur^e 
dans  les  liquides  de  I'organisme.     Bull,  de  la  Soc.  Chim.  (2),  48,  82  (1887). 

6  Berthelot  et  Andr^.  Contributions  k  I'histoire  de  la  decomposition  des  amides  par 
I'eau  et  les  acides  (5tendus.     Bull,  de  la  Soc.  Chim.  (2),  47,  840. 


Chemistry  21 

Kreidl/  a  boiling  solution  of  potassium  urate  begins  to  decompose 
after  twelve  hours,  even  in  an  atmosphere  of  nitrogen. 

Gerard,^  F.  and  L.  Sestini,^  and  Kreidl  ^  have  shown  that  many 
micro-organisms  decompose  uric  acid  to  urea.  Ulpiana  *  and 
Cingolani  ^  have  recently  isolated  and  prepared  pure  cultures 
of  a  micrococcus,  which  decomposes  uric  acid  quantitatively  into 
urea  and  COg  according  to  the  reaction :  C5H4O3N4  +  2  HjO  4-  30  = 
2  CO  (NH2)2  +  3  CO2. 

The  decomposition  of  uric  acid  into  glycocoll,  carbon  dioxide, 
and  ammonia  by  the  action  of  hydriodic  or  hydrochloric  acid  at 
160°,  first  shown  by  Strecker,®  is  an  important  one. 

Under  the  influence  of  the  oxygen  of  the  air,  an  alkaline  solu- 
tion of  uric  acid  changes  to  uroxanic  acid.^'*    Reaction: 

QH.NA  +  2H2O  +  O  =  QHgNA- 

In  neutral  or  alkaline  solution,  such  oxidizing  agents  as  lead 
peroxide,  manganese  dioxide,  potassium  ferricyanide,  cupric 
oxide,  mercuric  oxide,  ozone,  sodium  and  barium  peroxide,  potas- 
sium permanganate,  or  iodine,  change  uric  acid  to  allantoin.^ 


NH  — CO 

1           1 

NH  — ( 

:o    NH2 

CO       C  — NH\ 

1       II          )co 

NH  — C  — NH/ 

+ 

0  +  H2O     = 

=      CO 
NH  — C 

CO 
^H  — NH 

+ 

CO^ 

uric  acid 

allantoin 

1  J.  Kreidl.  Eine  Bestimmungsmethode  fur  Harnsaure  und  Beobachtungen  an  Harn- 
saurelosungen.     Monatshefte.  fiir  Chemie,  14,  111  (1893). 

2  Gerard.  Fermentation  de  I'acide  urique  par  les  microorganismes.  Comptes  rendiis, 
122,  1019  (1896)  and  123,  185  (1896). 

3F.  and  L.  Sestini.     Gaz.  Chim.  ital.,  20,  133. 

^  C.  Ulpiani.  Ueber  das  Bakterium  der  Harnsaure.  Atti  R.  Accad.  dei  Lincei.  Roma 
(5),  12,  II,  236;  Gaz.  Chim.  ital.,  33,  II,  93,  1903,  and  Chem.  Centralbl.,  1903,  II,  1287. 

'  M.  Cingolani.  Chemische  Gleichung  der  Garung  der  Harnsaure.  Gaz.  chim.  ital.,  33, 
II,  98,   1903;  Chem.  Centralbl.,  1903,  II,  1287. 

6  A.  Strccker.  Bildung  von  Glycocoll  aus  Harnsaure.  Liebig's  Ann.  der  Chem.  u. 
Pharm.,   146,   142  (1868). 

'  J.  Kreidl.  Eine  Bestimmungsmethode  fiir  Harnsaure  und  Beobachtungen  an  Harn- 
saurelosungen.     Monatshefte  fiir  Chemie,  14,  111  (1893). 

8  Staedeler.  Ueber  die  Uroxonsaure,  ein  Zersetzungsprodukt  der  Harnsaure.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  78,  286  (1851). 

Nencki  und  Sieber.   Ueber  die  Zersetzung  des  Traubenzuckers  und  der  Harnsaure  durch 
Alkalien  bei  der  Bruttemperatur.     Jour,  fiir  Prakt.  Chem.,  2  (24),  503  (1881). 
V.  Schroder.     Beitrage  zur  Physiologie.     C.  Ludwig,  94  (1887). 

9  W.  Kruger.  Eine  neue  Methode  zur  Bestimmung  der  Harnsaure  im  Harn.  Zeitschr. 
fiir  physiol.  Chem.,  21,  311  (1895).  A.  Claus.  Zur  Kenntniss  der  Harnsauregruppe. 
Ber.  der  Dtsch.  chem.  Gesell.,  7,  226  (1874).  E.  Bryk.  Ueber  die  Einwirkung  von  Jod 
und  Kalilauge  auf  Harnsaure.     Monatshefte  fiir  Chemie,  15,  519,  1894. 


22      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 


According  to  Sundwik/  by  the  oxidation  of  uric  acid  in  alkaline 
solution,  we  get  first  a  certain  compound,  from  which,  by  further 
oxidation,  uroxanic  acid  is  obtained  when  the  solution  is  evapo- 
rated to  dryness  or  allowed  to  stand,  and  from  which  allantoin  is 
obtained  if  the  alkali  is  neutralized,  viz., 


NH  — CO 

I  I 

CO       C  — NH 

II  11 

NH  — C  — NH- 
A         uric  aci(ijV 


;C0 


NH— CO 

I  I 

CO       C(OH)— NH\ 


NH— C(OH)— NH/ 
intermediate  product 


NH  — CO 

CO       C(OH)  — NH\ 

NH  — C(OH)— NH/ 

intermediate  product 

N   —  COONa 
/,  CO       C(OH)— NH- 


;C0 


C(OH)  —  NH 


CO  uroxanic  acid 


NH 
NH 

'CO        CO  — NH 
NH  — CH  — NH/ 
Behrend  ^  believes,  too,  that  this  same  intermediate  product  is  formed 


;C0 


alloxantin 


and'gives  evidence  that  the  further  oxidation  is  as  follows : 

NH— CHOH 


NH  — CO 

CO       C(OH)  — NH\ 

I  I  ) 

NH  — C(OH)  — NH/ 

intermediate  product 


NH, 
CO 


NH— C(OH)— NH 

glycoluriloxycar-     \ 
bonic  acid 


NH— C(OH)— NH 


or 

CHOH— NH 

I 
CO 


NH  —  C(OH)  — NH 


or 
COOH 


NH 

CO 
NH 


C  —  NH 

CO 

I 

CO    NH, 


1  E.   Sundwik.     Ueber  die  Bildung  von   Uroxansaure   und  Allantoin  aus  Harnsaure.   Zeitschr. 
fur  physiol.  Chem.,  41,  343   (1904). 

2  R.  Behrend.     Ueber  die  Oxydation  der  Harnsaure  in  alkalischer  Losung.     Liebig's  Ann.  der 
Chem.  u.  Pharm.,  333,  141  (1904). 


Chemistry 


23 


NH 

I 
CO 

I 
NH 

I 
CO 

I 
NH 


NH 
CO 
NH 


CHOH     NH.  NH— C(OH)NH. 

I      "   (-H3O)    I 
CO    >   CO 


NH  — CO      NH., 


C(OH)— NH 

or 
CHOH— NH 


NH— C 


CO 
NH 


CO 


CO 


I        (-H,0) 
CO >  CO 


NH2     C(OH)  — NH 


NH  — CH  — NH 

allantoin 

NH,     CO  — NH 


C(OH)— NH 
or 


COOH 


NH 
CO 
CO    NH, 


NH- 


NH 

-^  CO 
NH„ 


I 

co- 

C NH 

COOH 

C NH 

CO 
COOH    NH, 


CO 


CO 


NH— CH  — NH 


uroxamic  acid 


By  gradual  oxidation  of  uric  acid  in  acid  solution  with  cold 
concentrated  nitric  acid/  chlorine ,2  bromine,^  or  iodine,^  man- 
ganese dioxide  and  sulphuric  acid/  HCl  and  potassium  chlorate/ 
or  HIO3/  we  obtain  first  alloxan  and  urea.  On  heating,  the  al- 
loxan oxidizes  further  to  parabanic  acid  and  carbon  dioxide,^ 
Alkalies  change  the  parabanic  acid  to  oxaluric  acid/  which  can 
be  further  decomposed  to  oxalic  acid  and  urea  by  prolonged  boil- 
ing with  water.  This  series  of  changes  is  represented  graphically 
beloW : 


NH  — CO 


CO 

I 
NH 


C  — NH\ 
-C  — NH/ 

uric  acid 


CO 


NH  — CO 

I  I 

CO       CO- 

•I      I 

NH  — CO 

alloxan 


NH  — CO 

■^CO 

NH  — CO 

parabanic  acid 


NH,      COOH        COOH 


CO 

NH  —CO 

oxaluric  acid 


COOH 


oxalic  acid 


'  Liebig  und  Wohler.     Untersuchungen  iiber  die  Natur  der  Harnsaure.     Liebig's  Ann. 
der  Chem.  u.  Pharm.,  26,  256  (1838). 

2  G.  Brugnatelli.     Sur  un  acide  nouveau  obtenu  en  traitant  I'acide  urique  par  I'acide 
nitrique.     Annal.  de  Chim.  et  Phys.,  8,  201  (1818). 

3  M.  Hardy.     Decomposition  de  I'acide  urique  par  le  brome,  et  Taction  de  la  chaleur 
sur  alloxan.     Annal.  de  Chim.  et  Phys.  (4),  2,  372. 

*  G.    Wheeler.     Notiz   iiber   die    Einwirkung   von   Mangansuperoxyd   auf   Harnsaure. 
Zeitschr.  fiir  Chem.,  746  (1866). 

5  Laurent,  Gerhardt.     Annal.  de  Chim.  et  Phys.  (3),  24,  175. 

s  A.  Archette.     Einwirkung  von  Jodsaure  auf  Harnsaure.     Boll.  Cliim.  Farm.,  43,  394 
(1904),  and  Chem.  Centralbl.,  1904,  2,  318. 

'    Liebig  imd  Wohler.     Verhalten  des  Alloxans  beim  Seiden  mit  Wasser.     Liebig's  Ann. 
der  Chem.  u.. Pharm.,  38,  357. 


24     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Fehling's  solution  ^  and  alkali  tungstate  ^  likewise  oxidize  uric 
acid  to  oxalic  acid  and  urea. 

A  new  primary  oxidation  product  of  uric  acid,  tetracarbonimide, 

/NH.CO.NH\ 
C0(  )C0 

Xnh.co.nh/ 

has  been  obtained  by  Scholtz^  by  oxidation  with  hydrogen  peroxide. 
If  to  a  warm  solution  of  uric  acid,  nitric  acid  or  chlorine  water 
is  added,  and  the  solution  evaporated  to  dryness,  there  remains 
a  red  residue  which  becomes  purple  red  on  addition  of  ammonia.* 
This  is  murexid,  the  ammonium  salt  of  purpuric  acid. 

NH  — CO    NH     CO  — NH 

I         I  X     \l         I 
CO       C    C        CO 

II  II 

NH  — CO  CO  — NH 

The  nitric  acid  changes  uric  acid  to  alloxantin, 

NH— CO    O     CO— NH 

I          I    /  \l  I 

CO      C  C         CO 

NH  — CO  CO— NH 

and  ammonia  changes  the  alloxantin  to  murexid. 

Reduction  of  Uric  Acid.  —  Emil  Fischer  did  not  succeed  in 
reducing  ■  uric  acid  directly.  He  first  chlorinated  and  then  re- 
duced the  chlorine  derivatives  with  hydriodic  acid.  Tafel,^  in 
1901,  attempted  to  reduce  the  oxypurins  in  sulphuric  acid  solu- 
tion by  means  of  the  electric  current.  He  obtained,  not  purins 
but  saturated  bodies  which  he  called  purons.  They  were  neither 
acids  nor  bases. 

NH— CO  NH— CH^ 

CO     C  — NH\  CO     CH  — NH\ 

I  II  CO  I  I  CO 

NH    C  — Nh/  NH— CH  — NH/' 

uric  acid  puron 

1  Moritz.  Ueber  die  Kupferoxydreducirenden  Substanzen  des  Hams  unter  physiologi- 
schen  und  pathologischen  Verhaltnissen.     Archiv.  fiir  klin.  Med.,  46,  217  (1890). 

2  O.  Maschke.  I^eber  das  Verhalten  der  Wolframsaure  zu  einigen  Bestandtheilen  des 
Harns.     Zeitschr.  fur  anal.  Chem.,  16,  427  (1877). 

2  M.  Scholtz.  Ueber  ein  neues  Oxydationsprodukt  der  Harnsaure.  Ber.  der  Dtsch. 
chem.  Gesell.,  34,  4130  (1901). 

*  Liebig  und  Wohler.  Untersuchungen  liber  die  Natur  der  Harnsaure.  Liebig's  Ann. 
der  Chem.  u.  Pharm.,  26,  241  (1838). 

''  J.  Tafel.  Reduktionsprodukte  der  Harnsaure.  Ber.  der  Dtsch.  chem.  Gesell.,  34,  258 
(1901). 


Chemistry 


25 


He  prepared  and  studied  a  number  of  bodies  of  this  class.  In 
another  research  ^  he  found  that  the  methyl  derivatives  of  uric 
acid  act  in  the  same  way  and  give  methyl  purons,  a  number  of 
which  he  prepared  and  studied.  Later,  he  studied  the  electro- 
lytic reduction  of  xanthin,^  guanin,^  caffein/  and  other  purin 
derivatives.^ 

Relation  of  Uric  Acid  to  Other  Members  of  the  Purin 
Group.  —  All  the  other  members  of  the  group  can  be  derived 
from  uric  acid.  The  preparation  of  the  principal  members  of  the 
group  from  uric  acid  and  their  relations  to  it  can  be  shown  by 
the  following  scheme.  The  substance  marked  over  the  arrow  in 
each  case  is  what  brings  about  the  change. 


NH— CO 

I  I 

CO       C  — NH\^ 

NH  — C  — NH^ 

uric  acid 


CNH, 


■NH\^ 
N— C  — N  -^ 

dichloradenin 


CCl 


POCl 
CO  ■ ^   CCl  C  — NH\ 

II        II  } 

N  — C  — N  ^ 

trichlorpurin 


KOH  at  100° 


CCl 


NH  — CO 


CCl       C  — NH 

N  —  C  —  N  ^ 
dichlorhypoxanthin 


N 


CCl 


^Q 


v 


^ 


N=COC,Hs 

I  I 
C,H.OC      C  — NH\ 

II  II  /CCl 
N  — C  — N  ^ 

2-6-8-diethoxychlorpurin 


'  Tafel.      Reduktion    Produkte    aus  methylirten  Harnsaure.      Ber.  der  Dtsch.    chem. 
Gesell.,  34,  279  (1901). 

2  J.  Tafel  und  B.  Ach.    Elektrolytische  Reduktion  des  Xanthins.    Ber.  der  Dtsch.  chem. 
GeseU.,  34,   1165  (1901). 

3  Tafel  und  Ach.    Reduktionsprodukte  aus  Guanin.     Ber.  der  Dtsch.  chem.  Gesell.,  34, 
1170  (1901). 

*  J.  Tafel   und   A.   Weinschenk.       Ueber   3-methyl-desoxyxantbin   and   desoxyhetero- 
xanthin.     Ber.  der  Dtsch.  chem.  Gesell.,  33,  3369  (1900). 

•■*  J.  Tafel.     Ueber  Desoxytheobromin.     Ber.  der  Dtsch.  chem.  Gesell..  32,  3194  (1899). 


26     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 


N  =  CNH„ 

I  I 

CCl   C  — NH\ 

II  II  ) 

dichloradenin 


CH 


NH  — CO 

I  I 

CCl       C  — NH 

II  II  . 
N   —  C  —  N  ^ 

dichlorhypoxanthin 


N  =  COC2H5 
C,H,OC       C  — NH 


N=CNH, 

HI  I         I        ^ 

CCl     ^      CH    C  — NH\ 

II        II  ) 

N  — C—  N  ^ 

adenin 

,      NH  — CO 

V         I  I 

\c^o<^%CNH,C-NHn. 

^^<>  X    II         II  ^CCl- 

N  ^ 


HI 


NH— CO 
->CNH,  C  — NHv 


N 


C 

chlorguanin 


N 


C—  N  ^ 

guanin 


CH 


N  —  C—  N   ^ 

2-6-8-diethoxycblorpuriii 


CCl 


HI 


NH  — CO 

I  I 

CH       C  — NH\ 

II  II  ) 

N  —  C  — N  ^ 

hypoxanthin 
NH  — CO 
CO       C  — NH^ 

■C—  N  ^ 

xanthin 


CH 


CH 


NH 


Preparation  of  Uric  Acid.  —  For  the  preparation  of  uric  acid 
in  large  amounts,  either  snake  excrement  or  guano  is  used.  Ac- 
cording to  Bensch's  ^  method,  the  uric  acid  is  extracted  with 
potassium  hydrate  and  purified  by  precipitation  with  strong  acid. 
In  Strecker's  ^  method,  Hme  water  is  used  for  extraction,  and  the 
uric  acid  purified  by  a  method  similar  to  that  of  Bensch.  Ludwig,' 
Salkowski,^  Hopkins,^  and  Kriiger  and  Wulff,^  have  given  us 
methods  of  obtaining  uric  acid  from  human  urine,  and  Knieriem,^ 

1  A.  Bensch.  Ueber  einiger  Salze  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
54,  189  (1845). 

2  A.  Strecker.  Untersuchungen  liber  die  chemischen  Beziehungen  zwischen  Guanin, 
Xanthin,  Theobromin,  Caffein,  und  Kreatinin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  118, 
151  (1861). 

3  E.  Ludwig.  Zur  quantitativen  Bestimmung  der  Harnsaure.  Zeitschr.  fur  anal.  Chem., 
21,  148  (1882).     Wiener  Med.  Jahrbiich.,   1884,  599. 

Also,  Ueber  die  Bestimmung  der  Harnsaure.     Zeitschr.  fur  anal.  Chem.,  24,  637  (1885). 

*  E.  Salkowski.  Weitere  Beitrage  zur  Kenntniss  der  Leukamie.  Virchow's  Archiv, 
52,  58  (1871). 

5  Hopkins.     Bestimmung  von  Harnsaure  im  Harne.     Chem.  Centralbl.,  1892,  2,   269. 

8  Kriiger  und  Wulff.  Ueber  eine  Methode  zur  quantitativen  Bestimmung  der  sogen- 
annten  Xanthinkorper  im  Harne.     Zeitschr.  fiir  physiol.  Chem.,  20,  176,  1895. 

'  W.  Knieriem.  Ueber  das  Verhalten  der  im  Saugethierkorper  als  Vorstufen  des  Harn- 
stoffs  erkannten  Verbindungen  zum  Organismus  der  Hiihner.    Ztsch.  fiir  Biol.,  13,  36  (1877). 


Chemistry  27 

Meissner/  and  Bensch  ^  for  the  isolation  of  uric  acid  from  bird's 
urine. 

Qualitative  Tests  for  Uric  Acid.  —  If  nitric  acid  or  chlorine 
water  is  added  to  a  solution  of  uric  acid  and  the  solution  evapo- 
rated to  dryness  on  the  water  bath,  there  remains  a  reddish 
residue  which  is  changed  to  purple  red  with  ammonia.  Sodium 
h3^droxide  or  potassium  hydroxide  will  change  this  to  reddish 
blue.^  This  is  the  murexid  test,  and  is  explained  a  few  pages 
back.     The  presence  of  succinic  or  kynurenic  acid  spoils  the  test.* 

If  uric  acid  be  warmed  with  a  few  drops  of  nitric  acid,  and  then 
mixed  in  the  cold  with  a  few  drops  of  the  chlorhydrate  of  dimethyl- 
paraphenylendiamin  in  1  or  2  per  cent  aqueous  solution,  there 
appears  a  purple  red  color,  which,  on  warming  and  evaporating, 
changes  to  violet  blue.  This  color  disappears  on  cooling,  but 
again  reappears  on  warming.^ 

Another  way  of  testing  for  uric  acid  is  to  warm  the  substance 
to  be  tested  with  nitric  acid  or  bromine  water  until  it  boils,  and 
then,  after  evaporation,  to  add  two  or  three  drops  of  concentrated 
sulphuric  acid  and  a  few  drops  of  commercial  benzene  (containing 
thiophene).  The  presence  of  uric  acid  is  shown  by  a  blue  color, 
which  changes  to  brown  on  evaporation  of  the  benzene,  and  again 
reappears  on  addition  of  the  benzene." 

Confirmatory  tests  are  the  reduction  of  Fehling's  solution  and 
of  silver  nitrate  by  uric  acid,  and  the  formation  of  a  blue  color  on 
treating  a  solution  of  uric  acid  with  phospho-tungstic  acid  or 
phospho-molybdic  acid.^ 

Quantitative  Determination  of  Uric  Acid.  —  The  Ludwig- 
Salkowski  ^,  method  is  the  one  chiefly  used.  According  to  War- 
necke,"  Hopkins'  method  is  not  always  accurate.     This  method 

1  Meissner.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  thierischea  Organismus. 
Zeitschr.  fur  ration.  Med.  (3),  311,  144  (1868). 

2  A.  Bensch.  Ueber  einige  Salze  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
54,  189  (1845). 

3  Liebig  und  Wohler.  Untersuchungen  iiber  die  Natur  der  Harnsaure.  Liebig's  Ann. 
der  Chem.  u.  Pharm.,  26,  241  (1838). 

^  G.  Meissner  und  C.  Shepard.  Untersuchungen  iiber  die  Entstehung  der  Hippursaure 
im  thierischen  Organismus.     Hannover,  1866,  113  und  203. 

5  P.  Malerba.  Un  nuovo  metodo  per  riconoscere  I'acetone  e  racido  urico.  Atti  della 
R.  accad.  med.  e  chir.  di  Napoli.  Ao.  XLVIII,  Nuova  Serie  2,  from  Maly's  Jahresb. 
Ueber  die  Fortschritte  der  Thierchem.,  24,  76   (1894). 

s  G.  Denigfes.     Neue  Reaction  der  Harnsiiure.  Jour,  de  Pharm.  et  de  Chimie,  IS,  161,  162. 

'  See  Huppert  (Neubauer  u.  Vogel).     Analyse  des  Harns,  3d  ed.,  1898,  p.  331. 

*  Ibid.     Analyse  des  Hams,  3d  ed.,  p.  820. 

^  Warnecke.  Leber  die  quantitative  Bestimmung  der  Harnsaure,  etc.  Dissert.  Got- 
tingen.  (98). 


28     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

depends  upon  the  principle  that  uric  acid  in  the  presence  of 
ammoniacal  magnesia  solution  is  precipitated  as  double  salt  by 
an  ammoniacal  silver  solution.  The  uric  acid  is  dissolved  out  of 
the  double  salt  by  alkali  sulphide  and  then  reprecipitated  with 
hydrochloric  acid.  The  technique  of  the  method  is  found  in  the 
textbooks.^  The  methods  of  determining  uric  acid  will  not  be 
discussed  here. 

The  Methyl  Uric  Acids.  —  Although  the  methyl  uric  acids 
themselves  have  not  been  shown  to  be  of  any  physiological  im- 
portance, they  are  of  considerable  importance  in  the  study  of 
the  structure  of  uric  acid. 

i-)NH  — CO 
I  I 

CO       C— NH'-)\ 

I        II  )co 

3.)NH-C-NH,.)/ 

According  to  this  formula  for  uric  acid  we  should  expect  four 
mono-methyl  uric  acids,  the  methyl  groups  being  in  positions 
1,  3,  7,  and  9  respectively.  But,  in  fact,  we  have  six  mono- 
methyl  uric  acids .^  The  extra  ones  are  called  3  and  C  uric 
acid.  Fischer  and  others  have  thought  them  to  be  stereo- 
isomers, but  recently  Fischer  has  stated  that  stereo-isomerism 
could  not  explain  these  extra-methyl  uric  acids.  Behrend  and 
Dietrich  ^  thought  5-methyl  uric  acid  was  a  1-methyl  uric  acid, 
while  E.  Fischer  *  thought  it  a  3-methyl  uric  acid.  Later,  Beh- 
rend and  Thurm  *  confirmed  Fischer's  view  by  a  study  of  di- 
methyl-uracil  obtained  from  5-methyl  uric  acid. 

DIOXYPURIN  AND  DERIVATIVES 
Xanthin.  —  2-6-dioxypurin. 
NH— CO 

CO       C  — NH\ 

I  II  >CH 

Nil  — C—  N   ^ 

1  See  Huppert  (Neubauer  u.  Vogel).     Analyse  des  Hams,  3d  ed.,  1898,  p.  331. 

2  E.  Fischer  und  L.  Ach.  Ueber  die  Isomerie  der  Methylharnsauren.  Sitzungsberichte 
der  Konigl.  pr.  Akad.  Wiss.     Berlin,  35,  633  (1899). 

3  R.  Behrend  und  E.  Dietrich.  Ueber  die  Konstitution  der  3-Methylharnsaure.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  309,  260  (1899). 

*  R.  Behrend  und  R.  Thurm.  Ueber  die  Konstitution  der  Alkylderivate  des  Methyluracils 
und  der  5-Methylharnsaure.     Liebig's  Ann.,  323,  160  (1902). 


Chemistry  29 

In  1817,  Marcet*  found  xanthin  in  bladder  stones,  and  called 
it  xanthic  oxyd.  Wohler  and  Liebig  studied  its  composition,  and 
called  it  harnoxyd,  on  account  of  the  fact  that  it  contained  one 
less  atom  of  oxygen  than  uric  acid.  Its  presence  in  muscle  and 
pancreas  was  shown  by  Scherer.^ 

Strecker  ^  and  Scherer  *  first  found  xanthin  in  normal  urine. 
Pecile  ^  and  Salomon  ^  found  it  in  the  urine  of  swine,  and  Salomon  ^ 
in  dog's  urine.  Baginsky,^  Stadthagen,"  and  Weiske,^"  have  studied 
its  occurrence  in  urine  in  disease. 

The  best  practical  method  of  obtaining  xanthin  is  by  the  action 
of  nitrous  acid  on  guanin." 

Strecker  "  stated  that  xanthin  can  be  prepared  by  the  reduction 
of  uric  acid  with  sodium  amalgam,  but  E.  Fischer  *^  could  not 
confirm  this. 

The  experimental  proof  that  xanthin  is  a  reduction  product 
of  uric  acid  is  the  synthesis  of  xanthin  by  E.  Fischer.^^  Long 
before,  he  had  shown  its  decomposition  into  alloxan  and  urea  by 


1  An  Essay  on  the  Chemical  History  and  Medical  Treatment  of  Calcal  Disorders.  Lon- 
don, 19   (1817). 

2  Scherer.  Ueber  Hypoxanthin,  Xanthin,  and  Guanin  im  Thierkorper  und  den  Reich- 
thum  der  Pancreas-Druse  an  Leucin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  112,  257 
<1859). 

3  A.  Strecker.  Ueber  eine  neue  Base  aus  der  Fleischfliissigkeit.  Liebig's  Ann.  der  Chem. 
u.  Pharm.,  102,  204  (1857). 

Ueber  das  Sarkin.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  108,  129  (1858). 

Ueber  die  Verwandlung  des  Guanins  in  Xanthin.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
108,  141  (1858). 

''Scherer.  Xanthicoxyd  (Harnoxyd,  harnige  Saure),  ein  normaler  Bestandtheil  des 
thierischen  Organismus.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  107,  314  (1858). 

5  D.  Pecile.  Guanin  in  Schweineharn.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  183,  141 
(1876). 

8  G.  Salomon.  Ueber  die  chemische  Zusammensetzung  des  Schweinharns.  Du  Bois 
Arch.,  1884,  175. 

Ibid.     Virchow's  Archiv,  95,  527. 

'  Ibid.  Untersuchungen  uber  die  Xanthinkorper  des  Hams.  Zeitschr.  fiir  physiol. 
•Chem.,  11,  413  (1887). 

*  A.  Baginsky.  Leber  das  Verhalten  von  Xanthin,  Hypoxanthin,  und  Guanin.  Du 
Bois  Arch.,  1884,  176;  also  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxan- 
thin.    Zeitschr.  fur  physiol.  Chem.,  8,  397  (1884). 

9  M.  Stadthagen.  Ueber  das  Vorkornmen  der  Harnsaure  in  verschiedenen  thierischen 
Organen,  ihr  Verhalten  bei  Leukamie,  und  die  Frage  ihrer  Entstehung  aus  der  Stickstoff- 
basen.     Virchow's  Archiv,  109,  390  (1887). 

1°  Weiske.  Xanthin  und  Harnsaure  im  Ham  eines  kranken  Schlafbockes.  Zeitschr. 
fur  Biol.,  11,  254  (1875). 

"  Strecker.  Ueber  einige  Reduktionsprodukte  des  Allantoins  und  der  Harnsaure. 
Liebig's  Ann.  der  Chem.  u.  Pharm.,  131,  119  (1864). 

12  E.  Fischer,     l^eber  die  Harnsaure.     Ber.  der    Dtsch.  chem.  Gesell.,  17,  328  (1884). 

13  Ibid.  Synthese  des  Hypoxanthins,  Xanthins,  Adenins,  und  Guanins.  Ber.  der 
Dtsch.  chem.  Gesell.,  30,  2226  (1897). 


30      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

the  action  of  CI  and  HCl  solution  (analogous  to  the  decomposition 
of  uric  acid)  and  its  homology  with  theobromin  and  caffein.*  The 
lead  salt  changes  to  theobromin  (dimethylxanthin)  on  treatment 
with  methyliodide.^ 

Xanthin  can  be  synthetically  prepared  from  uric  acid  in  twc 
ways.  In  both  methods  trichlorpurin  is  first  formed  by  the  action 
of  PCI5  on  uric  acid. 

In  the  first  method  the  trichlorpurin  is  changed  to  2-6-dieth- 
oxy-8-chlor-purin 

N     =     COC2H5 

COaHs    C— NH\ 

II  II         )cci 

N      —     C—  N   ^ 

by  the  action  of  sodium  ethylate  (CjHjONa),  and  this  is  changed 
to  xanthin  by  the  action  of  HI.^  In  the  second  method,  the  tri- 
chlorpurin is  changed  to  diiodopurin  by  hydriodic  acid  at  0°  and 
then  to  xanthin  by  HCl.^ 

These  reactions  prove  the  structure  and  the  relation  to  uric 
acid.  For  the  recognition  of  xanthin,  its  change  to  caffein,  and,. 
as  analytical  test  also,  its  changes  to  brom-xanthin,  brom-caffein,. 
and  ethoxy-  and  hydroxy-caffein  are  used.^ 

Heteroxanthin.  —  7-methyl-xanthin. 

NH— CO 

I  I         /CH3 

CO     c— n( 

I  II  )CH 

NH  — C  — N^ 

Before  Fischer's  work  the  only  monomethyl  xanthin  known 
was  heteroxanthin.  This  was  found  in  human  urine  by  Salomon 
and  Kriiger.^  Gottlieb  and  Bondzynski,^  Albanese,^  and  Kriiger 
and  Salomon  *  have  studied  the  amounts  of  heteroxanthin  in  the 
urine  and  tissues  of  man  and  other  animals. 

1  E.  Fischer.  Ueber  Caffein,  Theobromin,  Xanthin,  und  Guanin.  Liebig's  Ann.  der 
Chem.  u.  Fharm.,  215,  253  (1882). 

2  Ihid.  Synthese  des  Hypoxanthins,  Xanthins,  Adenins,  und  Guanins.  Ber.  der  Dtsch. 
chem.  Gesell.,  30,  2226  (1897). 

^  Ihid.  Ueber  das  Purin  und  seine  Methylderivate.  Ber.  der  Dtsch.  chem.  Gesell.,  31,. 
2550  (1898). 

*  M.  Kriiger  und  G.  Salomon.  Die  Konstitution  des  Heteroxanthins  und  seine  physio- 
logischen  Wirkungen.     Zeitschr.  fiir  physiol.  Chem.,  21,  169  (1895). 

5  Gottlieb  und  Bondzynski.  Ueber  Methylxanthin,  ein  Stoffwechselprodukt  des  Theo- 
bromins  und  Caffeins.     Ber.  der  Dtsch.  chem.  Gesell.,  28,  1113  (1895). 

8  M.  Albanese.  Ueber  das  Verhalten  des  Caffeins  und  des  Theobromins  im  Organismus— 
Archiv.  fiir  exp.  Path.,  35,  449  (1895). 


Chemistry  31 

Kriiger  and  Salomon  proved  its  structure.  They  methylated 
it  to  caffein  and  changed  it  to  sarkosin  by  the  action  of  HCl. 
Fischer^  has  prepared  it  synthetically  from  theobromin.  POCI3 
at  140°  changes  theobromin 

NH  —  CO 

I  I  /CH3 

CO       c— nC 

I  II  )CH 

NCH3— c  — n/' 

to  7-methyl-2-6-dichlorpurin 

N  =CC1 

I  I  /CH, 

cci   c-^n( 

II  II  \CH 
N  —  C— N-/ 

and  this  is  changed  to  heteroxanthin 

NH— CO 

I  I  /CH3 

CO     c  — n( 

I  II  ^CH 

NH  — C  — N-/ 

under  the  influence  of  HCl  at  120°. 

1-Methyl-Xanthin  has  been  found  in  human  urine  by  Kriiger 
and  Salomon,^  and  in  the  autolysis  of  the  suprarenal  capsule  by 
Okerblom.^  It  has  not  yet  been  synthesized  or  its  structure 
definitely  proved. 

Theobromin.  —  3-7-dimethyl-2-6-dioxypurin 

NH  —  CO 

I  I  /CH3 

CO        c— n; 
I  II        \CH 

NCH3  —  C  —  N  /^ 

Theobromin  is  the  most  important  dimethylxanthin.  It  was 
first  found  in  cocoa  beans  by  Woskresensky  *  in  1842.  It  is 
difficultly  soluble  in  hot  water  or  alcohol,  but  easily  soluble  in 
ammonia.     It  forms  salts  with  acids.     The  silver  salt  gives  caffein 

1  E.  Fischer.  Ueber  das  Purin  und  seine  Methylderivate.  Ber.  der  Dtsch.  chera.  Gesell. , 
30,   2400   (1898). 

2  M.  Kriiger  und  G.  Salomon.  Die  Alloxurbasen  des  Harnes.  Zeitschr.  fiir  physiol. 
■Chem.,  24,  384  (1898). 

'J.  Okerblom.  Die  Xanthinkorper  der  Nebennieren.  Zeitschr.  fiir  physiol.  Chem., 
.28,  60   (1899). 

*  Woskresensky.  Ueber  das  Theobromin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  41,  125 
•(1842). 


CO 

CO 

NCH3- 

-co 

NCH3 

1 
CO 

32      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

with  methyl  iodide.^     Fischer  ^  showed  that  it  is  dimethylxanthin 
and  that  chlorine  changes  it  to  monomethylalloxan 

NH  —  CO 


and  monomethylurea. 


NH 

He  was  the  first  to  synthesize  it.^  He  treated  3-7-dimethyluric 
acid  (I)  with  POCI3  and  PCI5.  The  oxygen  in  position  6  is  re- 
placed by  chlorine  and  then  the  chlorine  is  replaced  by  an  amido 
group  with  ammonia.  The  structure  of  this  3-7-dimethyl-6- 
amino-2-8-dioxy-purin  (II)  follows  from  the  fact  that  damp 
chlorine  decomposes  it  to  guanidin.  By  the  action  of  POCI3  the 
oxygen  in  position  8  is  replaced  by  CI.  Reduction  of  this  chloride 
changes   it  to   3-7-dimethyl-6-amino-2-oxy-purin   (III) 

NH   —   CO  N     =     CNH2  N     =     CNH^ 

I  1  /CH3  I  I  /CH,  1  I  /CH3. 

CO  C-N    (  CO  C—   N   (  CO  C  — n( 

I  II  ^CO  I  II  \C0  I  II  )CH 

NCH3  — C  — NHX  NCH3  — C—  NH/  NCH3— c  — n/" 

I  II  III 

which  is  finally  changed  to  theobromin  by  nitrous  acid.  The 
nitrous  acid  replaces  the  amino  group  by  oxygen. 

Two  other  simple  syntheses  of  theobromin  have  been  worked 
out  by  Ach  and  Fischer.*  The  first  consists  in  changing  3-7- 
dimethyluric  acid 

NH  —  CO 

I  I  /CH3 

CO  C  —  N  ( 

I  II  )co 

NCH,  — C  — NH/ 

*  A.  Strecker.  Untersuchungen  iiber  die  chemischen  Beziehungen  zwischen  Guanin,. 
Xanthin,  Theobromin,  Caffein,  und  Kreatinin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  118, 
151  (1861). 

2  E.  Fischer.  Umwandlung  des  Xanthins  in  Theobromin  und  Caffein.  Ber.  der  Dtsch. 
chem.  Gesell.,  15,  453  (1882). 

Ibid.  Ueber  Caffein,  Theobromin,  Xanthin,  und  Guanin.  Liebig's  Ann.  der  Chem.. 
u.  Pharm.,  215,  253  (1882). 

3  Ibid.     Synthese  des  Theobromins.    Ber.  der  Dtsch.  chem.  Gesell.,  30,  1839  (1897). 

■•  E.  Fischer  und  I^.  Ach.  Weitere  Synthesen  von  Xanthinderivaten  aus  methylirten 
Harnsauren.     Ber.  der  Dtsch.  chem.  Gesell.,  31,  1980  (1898). 


Chemistry  33 


into  chlortheobromin 


NH- 

-CO 

1 

1            /CH, 

CO 

c— n( 
II        \cci 

NH- 

-c— n/' 

by  boiling  with  POClg  and  then  replacing  the  chlorine  by  hydrogen 
in  the  usual  way. 

In  the  second  method,  3-methyluric  acid 

NH  —  CO 

CO         C— NH\ 

I  II         )co 

NCH3  — C  — NH/ 
is  first  changed  to  3-methylchlorxanthin 
NH  —  CO 
CO  C— NH\ 

I  II         )cci 

NCH3  — C  —  N^ 

by  the  action  of  PCI5,  and  then  methylated  to  chlortheobromin 

NH  —  CO 

I  I  /CH3 

CO        c  — n( 

I  II       >cci 

NCH3  — c  — n^ 

The  chlorine  compound  is  then  reduced  with  hydriodic  acid  to 
theobromin. 

Since  3-methyl  uric  acid  can  be  formed  by  direct  methylating 
of  the  uric  acid,  we  are  now  able  to  obtain  theobromin  directly 
from  it.  This  method  shows  its  structure  and  relation  to  uric 
acid. 

Theophyllin.  —  l-3-dimethyl-2-6-dioxypurin 

NCH,— CO 


CO 

C- 

-NH\ 

)CH 

NCH, 

—  C 

-N^ 

This  was  prepared  by  Ach  and  Fischer  ^  by  treating  1-3-di- 
methyluric  acid 

1  E.  Fischer  Snd  L.  Ach.     Synthese  des  Caffeins.    Ber.  der.  Dtsch.  chem.  Gesell.,  28,  3135 
(1895). 


34     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

NCH3— CO 

CO  C— NH\ 

I  II  /CO 

NCH3— C  — NH/ 

with  POCI3  and  PCI5.     The  chlor-theophyllin 
NCH3— CO 

CO  C  — NH\ 

I  II  /CCl 

NCH3  — C  —  N  ^ 

thus  formed  was  reduced  to  theophyllin  by  the  action  of  hydriodic 
acid.  This  was  the  first  derivative  of  xanthin  synthetically 
prepared.  It  was  discovered  in  tea  in  1888  by  Kossel.^  He 
showed  that  it  could  be  methylated  to  caffein  and  that  damp 
chlorine  changed  it  to  dimethylalloxan. 

Paraxanthin.  —  l-7-dimethyl-2-6-dioxypurin. 

NCH3  — CO 

I  I  /CH3 

CO        c  — n( 

I  II  )CH 

NH   —   C  — N-/ 

Paraxanthin  was  found  in  urine  by  Thudicum  in  1879,^  and  in- 
dependently by  Salomon,^  who  studied  it  chemically,  and  who, 
with  Kruger  *  studied  its  occurrence  in  urine  carefully.  Emil 
Fischer  synthesized  it  and  proved  its  structure.  It  is  changed 
to  caffein  by  the  action  of  hydriodic  acid.^  The  position  of  the 
two  methyl  groups  follows  from  Fischer's  first  synthesis  from 
theobromin,"^ 

1  A.  Kossel.  Ueber  eine  neue  Base  aus  dem  Pflanzenreich.  Ber.  der  Dtsch.  chem. 
Gesell.,  21,  2164  (1888). 

Ihid.  Ueber  das  Theophyllin,  einen  neuen  Bestandtheil  des  Thees.  Zeitschr.  fiir 
Physiol.  Chem.,  13,  298  (1889). 

2  G.  Thudicum.  Untersuchungen  iiber  die  Xanthinkorper  des  Hams.  Zeitschr.  fiir 
physiol.  Chem.,  11,  415  (1879). 

3  G.  Salomon.     Beitrage  zur  Chemie  des  Hams.     Du  Bois  Archiv,  1882,  426. 

Ihid.  Uber  das  Paraxanthin  einen  neuen  Bestandtheil  des  normalen  menschlichen 
Hams.     Ber.  der  Dtsch.  chem.   GeseU.,  16,  195  (1883). 

Ihid.  Ueber  das  Paraxanthin  einen  neuen  Bestandtheil  des  normalen  menschlichen 
Hams.     Zeitschr.  fiir  klin.  Med.  7,  Suppl.  Heft,  63  (1884). 

Ihid.  Ueber  Paraxanthin  und  Heteroxanthin.  Ber.  der  Dt-sch.  chem.  GeseU.,  18, 
3406  (1885). 

*  Kriiger  und  Salomon.  Die  Konstitution  des  Heteroxanthins  uad  seine  physiologischen 
Wirkungen.     Zeitschr.  fiir  physiol.  Chem.,  21,  169  (1895). 

5  E.  Fischer  Synthese  des  Heteroxanthins  und  Paraxanthins.  Ber.  der  Dtsch.  chem. 
GeseU.,  30,  2409  (1897). 


Chemistry  35 

NH  —  CO 

I  I  /CH3 

CO  C  — N  ( 

I  II  )CH 

NCH3  — c  — n/^ 
This  is  changed  to  7-methyl-2-6-diehlorpurin 

N  =  CC1 

II  /CH3 
CCl  C  — n( 

II        II  )CH 

N— C— N^ 

by  the  action   of   PCI5,  and  then  to  7-methyl-6-oxy-2-chlorpurin 

NH  — CO 

I  I  /CH3 
CCl     c  — n( 

II  II  )CH 

N  —  C  — N-/ 

by  replacing  one  of  the  chlorine  atoms  by  hydroxyl  with  KOH. 
This  is  methylated  to  l-methyl-2-chlor-6-oxy-7-methyl-purin 

NH— CO 

I  I  /CH3 
CCl     c  — n( 

II  II  ^CH 

N  —  C  — N^ 

Chlorin  is  replaced  by  oxygen,  giving  paraxanthin. 

NCH3— CO 

i  I  /CH3 

CO        c  — n( 

I  II  ^CH 

NH  —  C  — N/" 

By  a  second  method  of  Fischer's/  1-7-dimethyl  uric  acid 

NCH3  — CO 

I  I  /CH3 

CO  C  —  N    ( 

I  II  ^co 

NH  —   C  — NH/ 
is  obtained  by  condensation  of  urea  and|monomethyl-alloxan 

CH,N  — CO 

"I        I 
CO  CO 

II 

HN— CO 

1  E.  Fischer  und  H.  Clemm.     Neue  Synthese  des  Paraxanthins.     Ber.  der  Dtsch.  chem, 
Gesell.,  31,  2622  (1898). 


36     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

The  dimethyl  uric  acid  is  changed  to  chlorparaxanthin 

CH3N— CO 

I        I  /CH3 

CO  c  — n( 

I      II  cci 

HN— C— N/' 

with  phosphorus  oxy chloride,  and  this  reduced  to  paraxanthin 
with  hydriodic  acid.     Both  methods  prove  the  structure. 
Caffein.  —  l-3-7-trimethyl-2-6-dioxypurin. 

CH3N  — CO 

II  /CH3 

CO  c  — n( 

■         I        II  )CH 

CH3N  — c  — n/^ 

Caffein  was  discovered  in  coffee  in  1821  by  Robiquet  and  Pelle- 
tier  and  Caventou.^ 

Oudry^  found  thein  in  tea,  and  Jobst^  showed  that  caffein  and 
thein  are  identical.  Stenhouse  ^  first  showed  that  caffein  is 
chemically  related  to  the  uric  acid  derivatives.  By  oxidation 
with  HNO3  he  obtained  a  body  similar  to  murexid,  which  Ger- 
hardt  showed  to  be  dimethyl parabanic  acid.  Rochleder  ^  worked 
further  with  caffein  and  among  other  bodies  found  what  he  called 
amalinic  acid,  which  Strecker  ®  showed  to  be  alloxantin. 

E.  Fischer^  showed  the  decomposition  by  damp  chlorine 
into  dimethylalloxan 

CH3N— CO 

I       I 
CO   CO 

I    I 

CH3N  — CO 

1  Berzelius  Jahresberichte,   4,    180,  and  7,   269. 

^Oudry.     Thein,  eine  organische  Salzbase  im  Thee.     Mag.  fur  Pharm.,  19,  49  (1827). 

3C.  Jobst.  Thein  identisch  mit  Caffein.  Liebig's  Ann.  der.  Chem.  u.  Pharm.,  25,  63 
(1838). 

*  J.  Stenhouse.  Ueber  Thein  und  seine  Darstellung.  liebig'a  Ann.  der  Chem.  u.  Pharm., 
45,   366    (1843). 

Ihid.  Nachtragliches  iiber  das  Thein.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  46,  227 
(1843). 

6  Rochleder.     Ueber  das  Caffein.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  71,  1  (1849). 
8  A.  Strecker.     Untersuchungen  iiber  die  chemischen  Beziehungen  zwischen  Guanin, 

Xanthin,  Theobromin,  Caffein,  und  Kreatinin.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  118, 
151  (1861). 

7  E.  Fischer.     Ueber  das  Caffein.     Ber.  der  Dtsch.  chem.  GeseU.,  14,  637  (1881). 
Ihid.,  14,  1905  (1881). 

Ihid.  Ueber  Caffein,  Theobromin,  Xanthin,  und  Guanin.  Liebig's  Ann.  der  Chem. 
u,  Pharm.,  215,  253  (1882). 


Chemistry  37 

and  monomethylurea 

NCH3 

I 
CO 

and  thus  proved  the  complete  analogy  to  uric  acid.  He  studied 
the  chemistry  of  caffein  much  further  and  finally  prepared  it  by 
methylating  xanthin,  and  proved  it  to  be  trimethylxanthin,  thus 
confirming  the  structure  proposed  by  Medicus. 

The  first  synthesis  was  that  of  Ach  and  Fischer.^     1-3-dimethyl 
uric  acid  is  changed  to  chlortheophyllin 
CH3N  — CO 

CO   C— NH\ 

I      II         )cci 

CH3N  — C  —  N  ^ 

by  the  action  of  POCI3  and  PCI5.  The  chlortheophyllin  is  methyl- 
ated to  chlorcaffein 

CH3N— CO 

■  I        I  /CH3 

CO    C  — N\ 

I  II  CCl 

CH3N  — c  — n/" 
and  the  chlorcaffein  reduced  to  caffein 

CH3N  — CO 

II  /CH3 
CO  c  — n( 

I       II  )CH 

CH3N  — C  — N-/" 

by  the  action  of  hydriodic  acid.^  Since  1-3-dimethyl  uric  acid 
itself  can  be  prepared  from  dimethylalloxan  or  dimethylmalonyl 
urea  the  complete  synthesis  is  possible. 

The  second  sjmthesis,^  which  was  the  first  synthesis  from  uric 
acid  itself,  consisted  in  methylating  uric  acid 

NH  — CO 

I  I 

CO       C— NH\ 

I       II  )co 

NH  — C  — NH/ 

1  E.  Fischer  und  L.  Ach.    Synthese  des  Caffeins.    Ber.  der  Dtsch.  chem.  Gesell.,  28,  3135 
(1895). 

2  E.  Fischer.     Ueber  Caffein,  Theobromin,  Xanthin,  und  Guanin.     Liebig's  Ann.  der 
Chem.  u.  Pharm.,  215,  253  (1882). 

Ibid.     Ueber  die    Tetramethylharnsaure.     Ber.  der  Dtsch.   chem.   Gesell.,   30,     3009 
(1897). 


38     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 
to  tetramethyl  uric  acid 

NCH3  —  CO  pTT 

CO  C  — N\ 

I  II       )co 

NCH3  — C  — N( 

\CH3 

and  then  changing  this  by  the  action  of  PCI5  to  chlorcaffein 

NCH3  — CO 

I  I  /CH3 

CO        c  — n( 

I  II        )cci 

NCH3  — C  — N^ 
and  finally  reducing  to  caffein 

NCH3  — CO 

I  I  /CK, 

CO        c  — n( 

I  II  )CH 

NCH3  — c  — n/^ 
with  hydriodic  acid. 

A  third   complete  synthesis  of  Fischer's   consists  in  heating 
1-3-7-trimethylpseudo-uric  acid 

CH3N  — CO 

CO   CHNCCHg)  CONH2 

CH3N— CO 

with  HCl.     This  gives  trimethyl  uric  acid 

CH3N  — CO 

I       I  /CH3 

CO  C  —  N  ( 

I     II  )co 

CH3N  — C— NHX 
which  can  be  changed  to  caffein 

CH3N  — CO 

II  /CH3 

CO   C  — N^ 

I        II  ^CH 

CH3N  — C  — N^ 

by  chlorination  and  reduction. 

Two  other  syntheses  which  show  the  connection  between 
caffein  and  uric  acid  have  been  worked  out  by  Fischer  and  Ach. 
One  leads  from  3-methyl  uric  acid 


Chemistry  39 


NH  - 

1 

-  CO 

1 

1 
CO 

NCH3- 

1 
c— 

II 

-c— 

NH\ 

)C0 
NH/ 

to  3-methyl-8-chlorxanthin 

NH   - 

-  CO 

CO 

1 
NCH3- 

c- 
-c  - 

-NH\ 

)CC1 

-N^ 

then  to  chlorcaffein 

NH   - 

CO 

1 
NCH3 

-  CO 

c- 
— c- 

/CH3 
-N^ 

)CC1 

which  is  easily  reduced  to 

caffein. 

NH  - 

1 
CO 

1 
NCH3 

-  CO 
C- 

—  C- 

/CH3 

-n( 

\CH 

In  the  second,  hydroxycaffein  is  obtained  by  direct  methylation 

of  uric  acid  in  aqueous  alkaline  solution.^ 

The  same  tautomerism  of  the  imidazol  ring  is  present  in  xan- 

thin  as  in  purin,  hypoxanthin,  and  adenin.     We  have  derivatives 

of 

NH  — CO 

I  I 

CO       C— NH\ 

I  II  )CH 

NH  — C  —  N  ^ 

and  might  expect  some  from 

NH  — CO 

I  I 

CO       C  —  N  ^. 

I  II  ^CH 

NH  — C— NH/ 

but  none  have  as  yet  been  prepared. 

The  other  methyl  derivatives  of  the  dioxypurins  are  not  of 
special  physiological  importance. 

1  E.  Fischer.     Synthese  des  Hypoxanthins,   Xanthins,  Adenins,  and  Guanins.     Ber. 
der  Dtsch.  chem.  GeselL,  30,  2226  (1897). 


40     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

MONOXYPURINS  AND  DERIVATIVES 
Hypoxanthin  (sarkin).  —  6  oxypurin. 
NH  — CO 

CH       C— NH\ 

II  II  )CH 

N  —  C—  N   ^ 

Hypoxanthin  is  the  only  naturally  occurring  monoxypurin. 
It  is  found  widely  distributed  in  the  animal  body.  It  was  found 
in  urine  by  Salkowski  ^  and  Salomon  ^  and  Pouchet.^  Thudicum/ 
Stadthagen,^  and  Baginsky  ^  have  studied  the  occurrence  of 
hypoxanthin  in  disease.  It  was  first  prepared  by  Scherer  in 
1850.'^  Strecker,^  Kossel,**  and  Kriiger^"  have  studied  its  struc- 
ture, but  this  was  finally  determined  by  Fischer.  He  treated 
uric  acid 

NH  — CO 


CO 


CO       C  —  NH 

NH  — C  — NH/ 

with   PCI5   and   obtained   trichlorpurin. 

N  ==CC1 

CCl     C  — NH\ 

II  II  /CCl 

N  —  C  —   N/ 


1  E.  Salkowski.  Beitrage  zur  Kenntniss  der  Leukamie.  Virchow's  Archiv,  50,  174 
(1870). 

*  Salomon.  Beitrage  zur  Lehre  von  der  Leukamie.  Reichert's  und  Du  Bois  Archiv, 
1876,  775.    Also 

Bietrage  zur  Chemie  des  Hams.     Du  Bois  Archiv,  1882,  426.      Also 

Untersuchungen  iiber  die  Xanthinkorper  des  Harna.      Zeitschr.  fiir  physiol.  Chem.,  11, 

410  (1887). 

3  Pouchet.     Contributions  k  la  connaisance  des  matiferes  extractives  de  I'urine.     Thfese, 

Paris,  1880. 

*  Thudicum.     Grundziige  der  anat.  u.  klin.  Chim.,  1886,  248. 

6  S.  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaure  in  verschiedenen  thierischen 
Organen,  ihr  Verhalten  bei  Leukamie,  und  die  Frage  ihrer  Entstehung  aus  der  Stickstoff- 
basen.     Virchow's  Archiv,  109,  390  (1887). 

6  A.  Baginsky.  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxanthin. 
Zeitschr.  fiir  physiol.  Chem.,  8,  398. 

'  Scherer.  Ueber  einen  im  thierischen  Organismus  vorkommen  den  dera  Xanthi- 
coxyd  verwandten  Korper.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  73,  328  (1850). 

8  A.  Strecker.     Ueber  das  Sarkin.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  108,  129  (1858). 

9  A.  Kossel.  L^eber  Xanthin  und  Hypoxanthin.  Zeitschr.  fiir  phys.  Chem.,  6,  428 
(1882). 

1"  M.  Kriiger.  Zur  Kenntniss  des  Adenins  und  Hypoxanthins.  Zeitschr.  fiir  physiol. 
.Chem.,  18,  445  (1894). 


Chemistry  41 

This  changes  to  6-oxy-2-8-dichlorpurin 
NH  — CO 
CCl      C  — NH\ 

II        II  )cci 

N  —  C  —  N  ^ 

by  the  action  of  aqueous  alkah.     Hydriodic  acid  changes  this  to 
hypoxanthin.^ 

NH  — CO 

CH      C  — NH\ 

II  II  /CH 

N  —  C   —  N  ^ 

Another  way  to  obtain  hypoxanthin  from  trichlorpurin  is 
through  adenin,  6-amino-purin.  This  changes  to  hypoxanthin 
on  treatment  with  nitrous  acid.  For  identification  we  can 
change  it  into  the  dimethyl  derivative  which  has  a  characteristic 
melting  point  and  compound  with  NaCl. 

The  methyl  derivative  of  the  monoxypurins  are  not  of  physio- 
logical importance. 

AMINO-PURINS 

Adenin.  — ^  This  is  the  only  important  monoaminopurin.  It 
is  widely  distributed  in  the  animal  kingdom.  Adenin  was  found 
by  Kossel,^  and  he  and  his  pupils  studied  it,  especially  the  well- 
known  change  to  hypoxanthin  on  treatment  with  nitrous  acid. 
HCl  at  200°  changes  it  to  glycocoll,  ammonia,  and  formic  acid  and 
carbon  dioxide.^  Bacteria,  like  nitrous  acid,  change  adenin  to 
hypoxanthin.^ 

Four  formulae  are  possible: 

1  E.  Fischer.  Synthese  des  Hypoxanthins,  Xanthins,  Adenins,  und  Guanins.  Ber. 
der  Dtsch.  chem.  Gesell.,  30,  2226  (1897). 

2  A.  Kossel.  Ueber  eine  neue  Base  aus  dem  Thierkorper.  Ber.  der  Dtsch.  chem.  Gesell., 
18,  79  (1885). 

Ibid.     Ueber  das  Adenin.     Ber.  der  Dtsch.  chem.  Gesell.,  18,  1028  (1885). 
Ibid.     Weitere  Beitrage  zur  Chemie  des  Zellkerns.     Zeitschr.  fiir  physiol.  Chem.,  10, 
250  (1886). 

Ibid.     Ueber  das  Adenin.     Zeitschr.  fiir  physiol.  Chem.,  12,  241  (1888). 

3  G.  Bruhns.  Ueber  Adenin  und  Hypoxanthin.  Ber.  der  Dtsch.  chem.  Gesell.,  23, 
225  (1890). 

M.  Kriiger.  Ueber  die  Konstitution  des  Hypoxanthins  und  des  Adenins.  Ber.  der  Dtsch. 
chem.  GeseU.,  26,  1914  (1893). 

*  S.  Schindler.  Beitrage  zur  Kenntniss  des  Adenins,  Guanins,  und  ihrer  Derivate. 
Zeitschr.  fur  physiol.  Chem.,  13,  432  (1889). 


42     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

N=CNH2  N=CNH2 

II  II 

CH  C— NH\  CH  C  —  N  ^ 

II        II  )CH  II       II  )CH 

I  II 

NH  — C=NH  NH— C  =  NH 

II  II 

CH      C  — NH\  CH      C  — N^ 

II  II  /CH  II  II  ;CH  I 

N_C—  N<^  N  —  C  — NH/ 
III  IV 

Only  two  methyl  derivatives  of  adenin  are  known.  They  have 
the  methyl  group  in  positions  7  and  9  respectively.  From  the 
indifference  of  these  methyl  compounds  to  alkalies,  we  can 
probably  exclude  formulse  III  and  IV,  for  the  presence  of  the 
imido  group  in  these  purin  bodies  makes  them  soluble  in  alkali. 
Formula  I  is  customarily  used  instead  of  Formula  II. 

There  are  two  ways  of  synthesizing  adenin  from  uric   acid. 

Uric  acid 

NH  — CO 

CO       C  —  NH  \ 

I  II  CO 
NH  —  C  —  NH  /^ 

can  be  chlorinated  to  trichlorpurin 

N  =  CC1 
CCl   C  — NHv 

1!      II  )cci 

N— C  —  N  ■/ 
and  the  trichlorpurin  changed  to  6-amino-2-8-dichlorpurin 

N  =  CNH3 
CCl    C  — NH\ 

II  II  >ci 

N_C  —  N  ^ 
with  ammonia,  and  finally  reduced  to  adenin 
N  =  CNH, 

CH    C  — NH\ 

II        II  )CH 

N  — C—  N  ^ 


Chemistry  43 

by  means  of  hydriodic  acid.^  This  method  shows  the  position 
of  the  amino  group.  In  the  other  synthesis,  uric  acid  is  changed 
to  8-oxy-2-6-dichlorpurin 

N  =  CC1 

I  I 

CCl    C  =  NH\ 

II  II  /CO 
N  — C  — NH/ 

by  PCI5,  and  this  is  changed  to  6-amino-8-oxy-2-chlorpurin 

N  =  CNH2 
CCl    C  — NH\ 

II      II  )co 

N  — C   —  N  ^ 

by  ammonia.  The  last  oxygen  atom  is  replaced  by  chlorine  and 
the  product  reduced  with  hydriodic  acid  to  adenin. 

N  =  CNH, 

CH    C  — NH\ 

II        II  )CH 

N  — C   —   N^ 

The  other  amino  purins  and  their  methyl  derivatives  are  not 
of  physiological  importance. 
GuANiN.  —  2-amino-6-oxypurin 

NH  —  CO 

CNH,   C  — NH\ 

II    'II        ;cH 

N    —    C  —  N  ^ 

Guanin,  the  most  important  amino-oxypurin,  was  discovered 
by  Unger  ^  in  guano.  It  was  found  in  human  urine  by  Pouchet,^ 
especially  in  certain  diseases,  and  by  Pecile  ^  in  the  urine  of  swine. 

1  E.  Fischer.  Synthese  des  Hypoxanthins,  Xanthins,  Adenins,  und  Guanins.  Ber.  der 
Dtsch.  chem.  Gesell.,  30,  2226  (1897). 

2  B.  Unger.  Ueber  das  Xanthin.  Poggendorf's  Ann.  der  Physik.  u.  Chemie,  65,  222 
(1845). 

Ibid.  Ben\erkungen  zu  eineni  Notiz  iiber  die  Zusammensetzung  des  Harnoxyd  von 
Embrodt.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  58,  20  (1846). 

Ibid.  Das  Guanin  und  seine  Verbindung.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  59, 
58  (1846). 

3  Pouchet.  Contributions  5,  la  connaisance  des  matiferes  extractives  de  I'urine.  Thfese, 
Paris,  1880,  Parent,  28  u.  36. 

*  Pecile.  Guanin  im  Schweineharn.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  183,  141 
(1876). 


44     The  Chemistry,  Physiology ,  and,  Pathology  of  Uric  Acid 

Salomon^  and  Baginsky  ^  have  also  studied  the  occurrence  of 
guanin  in  urine. 

Virchow  ^  and  Mendelsohn  *  have  reported  cases  where  guanin 
nodules  similar  to  the  urate  concretions  found  in  human  beings 
were  found  in  hogs. 

Guanin  is  found  in  the  pancreas,  and  in  tea,  and  is  widely  dis- 
tributed in  nature.  It  is  insoluble  in  water,  alcohol,  and  ether. 
Acids  and  bases  act  upon  it,  forming  salts.  Silver  nitrate  precipi- 
tates it  from  solution.  Strecker^  discovered  and  studied  its 
change  to  xanthin  on  treatment  with  nitric  acid,  the  change  which 
shows  its  structure,  and  its  change  to  guanidin  on  treatment  with 
damp  chlorine.  It  can  be  synthesized  from  2-8-dichlorhypoxanthin. 


NH  —  CO 
!C1       C  —  NH  \ 

II        II  )cci 


i 


This  is  treated  with  ammonia  and  changedjto  2-amino-6-oxy-8- 
chlorpurin 

NH  —  CO 


A 


NH.,    C  — NH\ 

II      '    II  )cci 

N   —   C  —  N  ^ 

and  the  latter  reduced  with  hydriodic  acid  to  guanin. 
N  =  CH 
CNH^C  — NH\ 

II      II         ;CH 

N  —  C  —  N  -^ 
Bacteria,  like  nitrous  acid,  change  guanin  to  xanthin.® 

1  Salomon.  Ueber  die  chemische  Zusammensetzung  des  Schweinharns.  Du  Bois  Arch., 
1884,  175.  Also  Ueber  die  chemische  Zusanunensetzung  des  Schweinharns.  Virchow's 
Archiv,  95,  527  (1884). 

2  Baginsky.  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxanthin. 
Zeitschr.  fiir  physiol.  Cheni.,  8,  395. 

2  Virchow.  Ueber  Konkretionen  im  Schweinfleisch  welche  naturscheinlich  aus  Guanin 
Bestehen.     Virchow's  Archiv,  35,  359  (1866). 

*  W.  Mendelsohn.  On  Guanin  Gout  in  the  Hog,  and  its  Relation  to  the  Sodium  Urate 
Gout  of  Man.     Am.  Journ.  of  Med.  Sciences,  New  Series,  95,  109  (1888). 

6  Strecker.  Ueber  die  Verwandlung  des  Guanins  in  Xanthin.  Liebig's  Ann.  der  Chem . 
u.  Pharm.,  108,  141  (1858). 

6  S.  Schindler.  Beitrage  zur  Kenntniss  des  Adenins,  Guanins,  und  ihrer  Derivate. 
Zeitschr.  fiir  physiol.  Chem.,  13,  432  (1889). 


Chemistry  45 

7-Methyl  Guanin.— 

NH  — CO 
-       I  I  /CH3 

CNH3  c  — n( 

II  II  )CH        ■ 

N  —  C  — N./ 

This  was  found  in  urine  by  Kriiger  and  Salomon^  and  is  easily 
synthesized.^  The  same  authors  proved  its  identity  with  epi- 
guanin. 

The  other  amino-oxypurins,  the  thiopurins,  and  the  halogen 
derivatives  of  the  purins  are  not  of  special  physiological  signifi- 
cance. 

PURIN 

N  =  CH 

I  I 

CH    C  — NH\ 

II  II  >H 

N  — C  —  N  ^ 

Purin  itself  was  the  most  difficult  of  the  group  to  prepare. 
It  was  finally  obtained  by  Fischer  in  1898.^  He  treated  trichlor- 
purin  at  0°  C.  with  hydriodic  acid,  and  obtained  diodopurin, 
which  was  reduced  with  zinc  dust.  Purin  is  exceedingly  soluble 
in  water,  and  Fischer  thinks  that  its  great  solubility  may  be  the 
reason  it  has  not  been  isolated  from  animals  and  plants. 

THE  MONOUREIDES 

The  purin  derivatives  on  decomposition  and  oxidation  give 
many  of  the  different  monoureides  and  their  derivatives.  It  will 
be,  perhaps,  of  some  value  to  give  a  short  sketch  of  the  most 
important  of  these  monoureides. 

Allantoin 

NH  — CO      NH.. 


^O 


^O 


NH  — CH  — NH 

is  a  ureide  of  glyoxylic  acid,  that  is  glyoxylurea.     It  is  an  im- 
portant  oxidation   product   of   uric   acid   from   a   physiological 

1  M.  Kriiger  und  G.  Salomon.     Epiguanin.    Zeitschr.  fiir  physiol.  Chem.,  26,  389  (189S). 

2  E.  Fischer.     Synthese  des  Heteroxanthins  und  Paraxanthins.     Ber.  der  Dtsch.  chem. 
Gesell.,  30,  2400  (1897). 

Ibid.     Ueber  das  Purin  und  seine  Methylderivate.     Ber.  der  Dtsch.  chem.  Gesell.,  31, 
2550   (1898). 


46     The  Cheinistry,  Physiology ,  and  Pathology  of  Uric  Acid 

standpoint.  It  was  found  by  Prout^  in  the  urine  of  new-born 
children,  by  Naunyn  ^  in  an  ovarian  cyst,  by  Gusserow  ^  in  the 
urine  of  men,  by  Pouchet^  in  human  urine  in  pathological  condi- 
tions sometimes  in  considerable  amounts,  by  Moscatelli  ^  in  ascites 
fluid,  and  by  Minkowski  ^  and  others  in  the  urine  of  dogs  and  cats. 

Its  importance  will  be  fully  discussed  later. 

Parabanic  acid,  or  oxalylurea, 

NH  — CO 

I 
CO 

I 

NH  — CO 

is  obtained  by  oxidation  of  uric  acid  and  alloxan  by  nitric  acid.'^ 

It  can  be  prepared  synthetically  by  the  action  of  POCI3  on  oxalic 

acid.^ 

Oxaluric  acid 

NH2      COOH 

I 
CO 

I 

NH  —CO 
is  formed  by  the  action  of  alkali  or  of  bromin  on  parabanic  acid.'^ 
It  is  found  in  urine. ^ 

Barbituric  acid,  or  raalonylurea, 

NH— CO 

CO      CH. 

NH— CO 
is  obtained  by  heating  allantoin  with  HjSO^.^'' 

1  Prout.  Observations  on  the  Nature  of  Some  of  the  Principles  of  the  Urine.  Med. 
Chir.  Trans.,  Vol.  VIII,  p.  526  (1818). 

2  Naiuiyn.  Ueber  die  Chemie  der  Transudate  und  des  Eiters.  Arch,  f .  Anat.  u.  Physiol., 
185  (1865). 

3  Gusserow.  Zum.  Lehre  des  Stoffwechsels  des  Fotus.  Arch.  f.  Gynakologie,  III,  241 
(1871). 

*  Pouchet.  Contributions  h,  la  connaisance  des  matiferes  extractives  de  I'urine.  Thfese 
de  Paris,  1880,  28. 

s  R.  MoscatelU.  Beitrage  iiber  den  Zucker  und  Allantoin-Gehalt  im  Harn  und  in  der 
Ascitesflussigkeit  bei  Lebercirrhose.     Zeitschr.  fiir  physiol.  Chem.,  13,  202  (1889). 

6  Minkowski.  Untersuchungen  zur  Physiologic  und  Pathologic  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

'  F.  Wohler  u.  J.  Liebig.  Untersuchungen  tiber  die  Natvtr  der  Harnsaure.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  26,  241  (1838). 

8  M.  Grimaux.  Recherches  synthetique  sur  la  serie  urique.  Ann.  de  Chim.  et  de 
Physique,  (5)  11,  356  (1877). 

9  Schlunk.     Jahresberichte  iiber  die  Fortschritte  der  Chemie,  1866,  749. 

10  Finck.  Zersetzungsprodukte  des  Thioursaurem  Ammoniaks.  Ann.  der  Chem.  u. 
Pharm,,  132,  298  (1864). 


Chemistry  47 

'    Dialuric  acid,  or  tartronlyurea, 

NH  — CO 

I  I 

CO       CHOH 

I  I 

NH  — CO 

is  obtained  by  reducing  alloxan  with  zinc  and  HCl.^ 
Dilituric  acid,  or  nitromalonylurea, 

NH— eg 

CO       CHNO2 

1      I 

NH  — CO 
is  otained  by  nitration  of  barbituric  acid  with  concentrated  nitric 

acid.^ 

Uramil,  murexan,  or  amidomalonylurea, 

NH  — CO 

CO       CHNH2 

NH  — CO 

is  obtained  by  reduction  of  dilituric  acid  with  hydriodic  acid.^ 
It  can  be  oxidized  to  alloxan  by  nitric  acid. 
Alloxan,  or  mesoxalylurea, 

NH  — CO 

CO      CO 

I  I 

NH  — CO 

is  obtained  by  moderate  oxidation  of  uric  acid  or  alloxantin.^ 
Pseudo-uric  acid 

NH— CO 

CO       CH  — NH  — CONH, 

NH— CO 
is  used  in  the  synthesis  of  uric  acid.     Its  ammonium  salt  can  be 
obtained  from  uramil  and  urea.* 


1  Liebig  und  Wohler^Untersuchungen  iiber  die  Natur  der  Hamsaure.     Liebig's  Ann. 
d^r'Chem.  u.  Pharm.,  26,  241  (1838).  , .  ^.   ,      .  ^       n^. 

2  Baeyer.     Untersuchungen  iiber  die  Harnsauregruppe.      Liebig  s  Ann.  der  Chem.  u. 
Pharm.,'  130,   129   (1864). 

3  76rd      127,  199  (1863). 

4  E   Gremaux.     Sur  I'acide  pseudo-urique.     Bull,  de  la  Soc.  Chim.,  31,  53o  (18/9). 


48     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Purpuric  acid, 

NH  —  CO  CO  —  NH 

I            I      NH      I  I 

I            1/       \l  I 

CO       C C         CO 

NH  — CO  CO  — NH 

The  ammonium  purpurate  is  the  murexid  obtained  in  the  murexid 
test. 

Ueic  Acid  and  Urates  in  Solution 

Minkowski  ^  says  that  in  the  treatment  of  gout  especial  atten- 
tion has  been  directed  to  four  points: 

First  —  Decreasing  the  formation  of  uric  acid. 

Second  —  Hastening  its  excretion. 

Third  —  Hastening  its  oxidation. 

Fourth  —  Increasing  its  solubility  in  the  blood  and  in  the  tis- 
sues. 

After  considering  briefly  the  first  three  points,  he  says  in  speak- 
ing of  the  fourth,  that  the  greatest  value  in  the  treatment  of  gout 
has,  in  general,  been  laid  on  methods  of  increasing  the  solubility 
of  uric  acid.  The  fact  that  uric  acid  is  stored  up  in  gouty  con- 
cretions in  the  form  of  a  difficultly  soluble  compound  has  led  to 
attempts  to  get  rid  of  it  by  making  the  solubility  conditions  more 
favorable. 

It  is,  then,  of  the  greatest  importance  that  the  solubility  of 
uric  acid  and  its  important  salts  in  pure  water,  in  blood  serum, 
and  in  urine  should  be  known,  and  that  the  effect  of  different 
acids,  salts,  bases,  and  organic  compounds  on  the  solubility  should 
be  understood.  There  is  a  great  deal  of  misapprehension  on  this 
subject,  and  therapeutics  and  treatment  based  on  an  inaccurate 
and  false  knowledge  of  the  solubility  relations  of  uric  acid  should 
be  corrected. 

Aqueous  Solutions  of  Uric  Acid  and  the  Urates 
URIC  ACID 

In  Pure  Water.  —  The  values  given  in  the  literature  for  the 
solubility  of  uric  acid  in  pure  water  have  varied  considerably. 

Prout  and  Mitscherlich  found  that  one  part  of  uric  acid  dis- 
solves in  10,000  parts  of  water.     Henry  found  that  it  dissolves 

1  O,  Minkowski.  In  Von  Leyden's  Handbuch  der  Ernahrungstherapie,  Vol.  II,  p.  510. 
Leipaig,  1S9&. 


Chemistry  49 

in  1,720  parts  of  cold,  and  1,400  parts  of  boiling  water,  and  in 
1,000  parts  of  urine. ^ 

The  solubility  as  determined  by  Bensch^  was  the  value  held 
for  a  long  time.  His  results  give  the  solubility  of  uric  acid  as 
one  part  in  14,800  to  15,300  cold  water,  and  one  part  in  1,800  to 
1,900  of  hot  water.  For  the  determination  in  cold  water,  he 
boiled  water  containing  an  excess  of  uric  acid,  then  cooled  the 
solution  for  eight  days,  and  after  filtering  off  the  excess  of  uric 
acid,  evaporated  a  measured  volume  of  the  solution  to  dryness. 
Behrend  and  Roosen  ^  used  the  same  method  as  Bensch,  and 
found  the  solubility  of  uric  acid  one  part  in  10,000  of  water  at 
18.5°. 

In  1875,  Magnier  de  la  Source  *  showed  that  water  decomposes 
uric  acid  and  that  the  result  obtained  for  the  solubility  of  the 
acid  by  saturating  at  a  high  temperature  and  then  cooling  was  a 
function  not  only  of  the  final  temperature,  but  of  the  maximum 
temperature  and  of  the  length  of  time  the  acid  has  stood  in 
contact  with  the  water.  According  to  him,  the  following  two 
reactions  take  place: 

CsH.NA  +  2H,0  =  CO(NH2)2  +   C.H.Np, 

uric  acid  urea  dialuric  acid 

and  CgH.N.Og  +  2  H,0  +  0  =  C.H.N^Os 
uric  acid  uroxanic  acid 

Gigli^has  shown  that  uric  acid  can  change  completely  to  urea 
by  the  action  of  water  at  the  ordinary  temperature  after  a  number 
of  months. 

Blarez  and  Deniger  ^  found  that  if  the  solutions  were  saturated 
at  100°  and  then  cooled  to  the  temperature  at  which  the  solubility 
was  to  be  determined  they  obtained  varying  results,  dependent 
upon  the  time  during  which  the  solution  was  kept  at  100°,  and 
likewise  upon  the  time  of   cooling.     If  they  saturated  at  the  re- 

1  W.  Henry.     De  acido  urico  et  morbis  a  minia  ejus  secretione  ortis.     Edinburgh,  1807. 
Berzelius.     Lehrbuch  der   Chemie.     Wohler's  German  Translation,  3d  ed.,  184,  Vol. 

IX,   p.   409. 

2  Bensch.  Ueber  einige  Salze  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
54,  189  (1845). 

2  Behrend  luid  Roosen.  Synthese  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
251,   235    (1889). 

*  Magnier  de  la  Source.  Action  de  I'eau  sur  I'acide  urique.  Bull,  de  Soc.  Chim.,  23, 
483  (1875). 

5  T.  GigU.  Ueber  die  spontane  Umwandlung  der  Harnsaure  in  Harnstoff.  Chem. 
Zeitung,  25,  741. 

6  Blarez  et  Deniger.  Solubilite  de  I'acide  urique  dans  1  'eau.  Comptes  rendus,  104, 
1847  (1887). 


50     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

quired  temperature,  their  results  were  more  constant.  They 
likewise  found  that  the  water  became  saturated  in  a  short  time 
if  it  were  well  shaken.  The  amount  of  uric  acid  in  the  solution 
was  determined  by  titrating  the  solution  with  potassium  per- 
manganate. The  solubility  of  uric  acid,  according  to  them,  is  one 
part  in  16,700  at  20°  C. 

All  the  determinations  made  previous  to  1887  are  then  incor- 
rect, on  account  of  the  decomposition  of  the  uric  acid  by  boiling. 

According  to  Camerer,^  uric  acid  is  soluble  in  14,000  parts  of 
water  at  15°  C,  7,000  to  8,000  parts  of  water  at  37°  C,  and  of  2,000 
parts  of  boiling  water. 

Bunge  ^  confirmed  the  results  of  Camerer  for  the  body  tempera- 
ture, but  did  not  give  his  method  of  determination. 

Smale^  found  one  part  uric  acid  soluble  in  2,400  parts  of  water 
at  40°  C.  He  shook  an  excess  of  the  acid  with  water  at  40°  and 
weighed  the  undissolved  residue. 

Nicolais  *  shook  an  excess  of  uric  acid  with  water  at  18°  and  at 
37°,  and  weighed  the  undissolved  residue.  He  found  the  solu- 
bility to  be  one  part  in  16,300  of  water  at  18°  and  one  part  in 
13,900  of  water  at  37°. 

Huppert  ^  gives  the  solubility  of  uric  acid  as  one  part  in  16,000 
of  cold  water,  one  part  in  1,600  of  hot  water. 

His  and  Paul®  first  called  attention  to  the  fact  that  since  the 
solubility  of  uric  acid  is  so  small,  the  determination  in  the  ordinary 
way  would  probably  not  be  correct.  The  solubility  of  difficultly 
soluble  substances  is  greatly  affected  by  the  presence  of  impuri- 
ties in  solution.  They  showed  that  the  impurities  found  in  or- 
dinary distilled  water  very  considerably  change  the  solubility 
of  uric  acid. 

In  their  determinations  they  took  particular  pains  to  get  rid 
of  all  possible  sources  of  error.  They  used  especially  pure  uric 
acid  and  pure  v>?ater  prepared  with  especial  precautions.  The 
purity  of  the  water  was  attested  by  its  very  low  electrical  con- 

1  Camerer.  Zur  Lehre  von  der  Harnsaure  und  Gicht.  Deutsche  Med.  Wochenschrift, 
17,  10,  356   (1891). 

2  Bvmge.     Lehrbuch  der  physiol.  u.  pathol.  Chem.,  4th  ed. 

3  Smale.  Beitrage  zur  Kenntniss  der  Losungsbedingungen  der  Harsaxire  im  Harn. 
Centralbl.  fiir  Physiol.,  385  (1895). 

*  Nicolais.     Experimentelle  und   KUnischesii  ber  Urotropin.     Zeitschr.  fiir   klin.  Med., 

Bd.  37,  366  (1899). 

f       5  Neubauer  und  Vogel.     Analyse  des    Hams,  3t  ed.,  Wiesbaden,  188,  p.  314. 
V      6  jjis   und    Paul.     Physikalisch-chemische    Untersuchungen   uber   das   Verhalten   der 

Harnsaure  und  ihre  Salze  in  Losungen.     Zeitschr.  fiir  physiol.  Chem.,  31,  1  (1900). 


Chemistry  51 

ductivity  (0.8  —  1.0  X  lO"**).  The  vessels  used  were  very  resistant 
to  the  action  of  water,  on  account  of  the  fact  that  distilled  water 
attacks  ordinary  glass  and  dissolves  some  of  the  constituents  of 
the  glass. 

The  uric  acid  was  dissolved  by  shaking  with  water  at  the  tem- 
perature at  which  a  determination  of  the  solubility  was  desired, 
and  was  left  as  short  a  time  as  possible  in  contact  with  the  water 
after  saturation.  The  solubility  was  determined  by  weighing 
the  undissolved  residue.  The  electrical  conductivity  of  water 
purified  by  distillation  in  the  ordinary  way  was  found  to  be  about 
half  that  of  a  saturated  solution  of  uric  acid.  This  high  relative 
conductivity  indicates  that  the  amount  of  ammonia,  carbonic 
acid,  and  alkaline  silicates  and  carbonates  to  which  it  is  due  is 
enough  to  considerably  influence  the  solubility  of  the  uric  acid. 
They  found  the  solubility  to  be  one  part  in  39,480.  The  disso- 
ciation into  hydrogen  ions  and  negative  uric  acid  ions  is  about 
95  per  cent  in  a  saturated  solution. 

The  Effect  op  Acids  on  the  Solubility  of  Uric  Acid.  — 
We  find  many  statements  in  the  literature  to  the  effect  that  uric 
acid  is  more  soluble  in  strong  mineral  acids,^  H2SO4  and  HCl, 
than  in  pure  water.  We  do  not  find  this  statement  in  the  books 
of  Liebig,  Poggendorf ,  and  Wohler,  Berzelius-Wohler,  Beilstein, 
Bunge,  Neumeister,  and  Hoppe-Seyler.  Zabelin  ^  says  that  HCl 
has  no  influence  on  the  solubility  of  uric  acid. 

Xanthin,  guanin,  and  theobromin  are  amphioteric  electrolytes; 
that  is,  they  can  act  as  bases  and  form  salts  with  acids,  or  they 
can  act  as  acids  and  form  salts  with  bases.  A  saturated  solution 
of  theobromin  is  dissociated  to  the  extent  of  0.27  per  cent  into 
positive  hydrogen  ions  and  negative  theobromin  ions.^  The 
'dissociation  into  positive  theobromin  ions  and  negative  hydroxyl 
ions  is  only  one  millionth  of  its  dissociation  into  negative 
theobromin  ions  and  positive  hydrogen  ions,  or  about  one  ten- 

1  Fehling  Handworterbuch  der  Chemie,  1878,  Vol.  Ill,  p.  584.  Ladenburg  Handworter- 
buch,  1893,  Vol.  V,  p.  7.  ^ 

Rudel.  Zur  Kenntniss  der  Losungsbedingungen  der  Harnsaure  in  Ham.  Arch,  fiir 
exp.  Path.  u.  Pharmak.,  30,  469  (1892). 

Smale.  Beitrage  zur  Kenntniss  der  Losungsbedingungen  der  Harnsaure  in  Harn. 
Centralbl.  fiir  Physiol.,  9,  385  (1895). 

Hammarsten.     Lehrbuch  der  physiolbgischen  Chemie.     4t  Auflage,  1899,  p.  44. 

2  Zabelin.  Ueber  die  quantitative  Bestimmung  der  Harnsaure  im  Harn  mittelst  Salz- 
saure.     Liebig's  Ann.  Suppl.,  2,  p.  313  (1863). 

3  T.  Paul.  Untersuchungen  iiber  Theobronan  und  Koffein  und  ihre  Salzbildung. 
Arch,  der  Pharm.,  239,  48. 


52      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

thousandth  to  one  forty-thousandth  the  basic  dissociation  of 
anihn.^  Theobromin,  then,  is  more  soluble  in  either  acid  or 
alkali  than  in  pure  water. 

From  the  analogy  in  chemical  constitution  between  uric  acid, 
theobromin,  xanthin,  and  so  forth,  it  had  been  thought  that  uric 
acid  would  form  salts  with  acids  and  thus  be  more  soluble  in  them 
than  in  pure  water.  This  question,  of  course,  has  a  practical 
interest,  since  uric  acid  is  sometimes  determined  by  precipitating 
from  its  salts  with  acids,  and,  further,  we  must  first  know  the  effect 
of  acid  on  its  solubility  in  pure  water  before  we  can  arrive  at  any 
conclusions  regarding  the  solubility  of  uric  acid  in  physiological 
fluids. 

A  priori  we  should  expect  that  if  uric  acid  does  not  form  salts 
with  acids,  that  is  to  say,  if  it  has  acid  but  not  basic  properties, 
it  would  be  less  soluble  in  acids  than  in  pure  water.  All  acids 
are  dissociated  in  solution  to  a  greater  or  less  extent  into  the 
positive  ion  or  cation,  hydrogen,  and  the  negative  ion  or  anion, 
which  is  composed  of  the  rest  of  the  molecule.  Uric  acid, 
C5H4N4O3,  as  His  has  shown ,^  is  about  10  per  cent  dissociated  (in 
saturated  solution)  into  the  positive  hydrogen  ion  and  the  nega- 
tive ion  C5H3N4O3.  We  know  that  the  concentration  of  the 
anion  and  the  cation  are  determined  by  the  equation 


PXN_ 
U 


where  P  stands  for  the  concentration  of  the  positive  ion  and  N 
for  the  concentration  of  the  negative  ion,  and  U  for  the  undisso- 
ciated  part  of  the  acid.  K  is  a  constant  for  any  given  tempera-, 
ture  and  concentration  of  acid.  In  the  case  of  a  saturated  solu- 
tion, U  becomes  a  constant  equal  to  the  solubility  constant  of 
the  acid,  and  the  equation  becomes  P  X  N  =  KIT  =  K^^.  If  a 
dilute  mineral  acid,  for  example  HCl,  is  added  to  the  solution, 
P  increases  very  considerably,  for  mineral  acids  are  almost  com- 
pletely dissociated  at  moderate  dilution.  If  P  increases,  N  must 
decrease  in  order  that  P  X  N  remain  constant.     That  is,  the 

1  T.  Paul.     Untersuchungen  ilber  Theobromin  und  Koffein  und  ihre  Salzbildung.     Arch, 
der  Pharm.,  239,  48.     ' 

2  W.  His  und  T.  Paul.     Physikalisch-chemische  Untersuchungen  iiber  das  Verhalten 
der  Harnsaure  und  ihrer  Salze  in  Losungen.     Zeitschr.  fiir  physiol.  Chem.,  31,  1  (1900). 


Chemistry  53 

amount  of  dissociated  uric  acid  must  decrease,  and,  since  the 
solubility  of  the  undissociated  part  is  a  constant,  a  decrease  in 
the  undissociated  part  means  a  decrease  in  the  solubility  of  the 
acid.  In  other  words,  acids  should  decrease  the  solubility  of 
uric  acid  in  water. 

From  theoretical  considerations,  His^  came  to  the  conclusion 
that  solutions  of  strong  mineral  acids  in  concentrations  of  from 
about  normal  down  to  one  one-hundredth  normal  would  dissolve 
uric  acid  to  the  extent  of  about  one  part  in  43,600  of  solution. 
He  showed  by  experiment  that  his  calculations  were  correct. 
He  concluded  that  the  uric  acid  in  salts  in  aqueous  solution  can 
be  determined  by  precipitation  with  HCl,  if  certain  precautions 
are  taken.  A  correction  of  2  mg.  must  be  made  for  each  100  cc. 
of  solution  at  18°  C.  Klemperer  ^  found  that  the  presence  of 
considerable  carbonic  acid  decreases  the  solubility  of  uric  acid. 
This  is  what  we  should  expect  from  theoretical  reasons. 

With  concentrated  sulphuric  acid,  uric  acid  forms  a  crystalline 
salt.^  This  is  decomposed  by  water,  and  does  not,  therefore, 
exist  in  aqueous  solution. 

If  the  concentration  of  the  hydroxyl  ions  in  a  solution  is  "in- 
creased, its  solvent  action  for  uric  acid  is  increased.  In  a  saturated 
solution  of  uric  acid,  the  equation  H  X  N  =  KU  determines 
the  equilibrium,  where  H  is  the  concentration  of  the  hydrogen 
ions,  N  the  concentration  of  the  negative  uric  acid  ions,  and  KU 
a  constant;  Free  hydrogen  ions  and  free  hydroxyl  ions  cannot 
exist  together  in  a  solution  to  more  than  a  slight  extent.  Undis- 
sociated water  is  immediately  formed.  As  fast  as  hydrogen 
ions  disappear  by  union  with  hydroxyl  ions,  more  undissociated 
uric  acid  is  formed  in  order  that  H  X  N  should  remain  constant, 
and  more  undissolved  uric  acid  goes  into  solution.  Addition  of 
any  caustic  alkali  causes  increase  in  the  concentration  of  hy- 
droxyl ions,  for  alkalies  are  dissociated  into  the  positive  metallic 
ion  and  the  negative  hydroxyl  ion.  This  is  the  cause  of  the  in- 
creased solubility  of  uric  acid  in  alkalies. 


^  His  und  Paul.  Physikalisch-chemische  Untersuchungen  iiber  das  Verhalten  der 
Hamsaure  und  ihrer  Salze  in  Losungen.     Zeitschr.  fiir  physiol.  Chem.,  31,  64  (1900). 

^  Cfc.  Klemperer.  ^Jeitrage  zur  Erklarung  harnsaurer  Niederschlage  in  Urin.  Zeitschr. 
fiir  physik.  und  diat.  Therapie,  5,  48  (1901-2). 

3  Fritzsch.  Verbindung  von  Harnsaure  mit  Schwefelsaure.  Liebig's  Ann.  der  Cliem. 
u.  Pharm.,  28,  332  (1838). 


54     The  Chemistry,  Pathology,  and  Pathology  of  Uric  Acid 

Amorphous  and  Crystalline  Uric  Acid.  —  Bird  ^  thought 
that  amorphous  uric  acid  does  not  exist,  and  Simon  ^  considered 
it  rare. 

Fritzsch  ^  showed  that  if  serpent's  excrement  be  extracted  with 
borax  solution  and  the  uric  acid  precipitated  with  HCl,  according 
to  Bottger's  method  *  there  is  obtained  a  transparent  crystalline 
hydrate  of  uric  acid  and  two  molecules  of  water,  C5H4N4O3.2H2O. 
This  slowly  changes  to  the  more  transparent  form  on  standing. 
With  pure  urate  solution  he  could  not  get  these  transparent 
crystals;  the  uric  acid  precipitated  in  a  heavy  flocculent  amor- 
phous form,  but  he  believed  that  both  forms  have  the  same 
chemical  composition.  This  amorphous  variety  changes  to  the 
anhydrous  non-transparent  crystalline  modification  on  standing. 
Matignon  ^  showed  that  this  last  change  is  accompanied  by  an 
absorption  of  heat,  and,  since  Berthelot  has  shown  that  the 
change  of  a  precipitate  from  its  initial  to  its  final  state  is  always 
an  exothermic  change,  unless  there  is  a  gain  or  loss  in  the  number 
of  molecules  of  water  on  crystallization,  then  Matignon's  work 
indicates  that  the  precipitate  as  first  obtained  is  a  hydrate,  prob- 
ably that  of  Fritzsch.  This  work  should  be  confirmed  by  more 
careful  experiments. 

Attention  has  been  called  to  the  fact  that  we  cannot  tell  whether 
uric  acid  has  the  lactim  formula 

N  =  COH 

I  I 
COHG  — NHs 

II  II  )C0H 

or  the  lactam  formula 

NH  — CO 

II 

CO       C  — NH\ 

I        II  )co 

NH  — C— NH/ 
According  to   Emil  Fischer,   both  forms   probably  exist.     The 

1  Eckstein.  Bibliothek  des  Ausland  fiir  die  organisch-chemische  Ruhlung  der  Heil- 
kunde,  1844,  2,  31. 

2  Simon.  Beitrage  zur  physiologische  und  pathologische  Chemie  und  Mikroscopie,  1, 
p.  97. 

3  Fritzsch.  Ueber  ein  krystallisirtes  Hydrat  der  Harnsaure.  Jour,  fiir  prakt.  Ghem., 
17,  56  (1839). 

■*  Bottger.     Beitrage  zur  Physik  und  Chemie,  p.  6. 

s  M.  Matignon.  Sur  I'hydrate  d'acide  urique.  Bull,  de  la  Soc.  Chim.  (3),  11,  571 
(1894). 


Chemistry  55 

lactam  formula  does  not  explain  the  acid  properties  of  uric  acid; 
the  lactim  formula  does.  The  existence  of  six  monomethyl  uric 
acids  can  be  explained  on  the  assumption  that  both  the  lactim 
and  the  lactam  forms  exist.  Fischer  thinks  that  the  finely 
divided  hydrate  precipitated  from  urate  by  acids  in  cold  solution, 
the  precipitate  investigated  by  Matignon,  is  a  hydrate  having 
the  lactim  formula,  and  that  the  anhydrous  acid  formed  through 
the  influence  of  water  on  standing  has  the  lactam  fornmla.  Tuni- 
cliffe  and  Rosenheim  ^  think  that  the  transparent  crystals  ob- 
tained by  Fritzsch  represent  an  intermediate  stage  between  the 
lactim  and  the  lactam  formula. 

THE     URATES 
The  lactim  formula  of  uric  acid 

N  =  COH 

I  I 

COH    C  — NH\ 

II  II  ^COH 
N  —  C  —  N  ^ 

is  the  one  which  accounts  for  its  acid  properties.  There  are  three 
hydrogen  atoms  which  we  might  possibly  suppose  replaceable 
by  bases.  We  have,  however,  no  tribasic  salts.  This  is  not 
strange,  for  often  the  tribasic  salts  of  weak  acids,  for  example, 
phosphoric  acid,  do  not  form  in  solution.  The  dissociation  of 
the  third  hydrogen  ion  is  comparable  with  the  dissociation  of  the 
water,  and  consequently  a  tribasic  salt  would  be  immediately 
decomposed  by  water.  We  do  have,  however,  monobasic  and 
dibasic  urates. 

The  urates  containing  two  molecules  of  the  base  were  called 
neutral  urates  by  Bensch,^  and  those  containing  one  atom  of  the 
base  acid  urates.  The  latter  are  often  called  biurates.  Tollens  * 
proposes  the  more  rational  names  mono-  and  di-urate  for  the 
salts  containing  respectively  one  and  two  atoms  of  the  base,  and 
for  the  hypothetical  quadriurate  supposed  to  contain  less  base 
than  the  mono-urate  he  proposed  the  name  hemi-urate. 

1  Tunicliffe  and  Rosenheim.  Contributions  to  oiir  Knowledge  of  Uric  Acid  Salts. 
Lancet,  1900,  1708. 

2  A.  Bensch.  Ueber  einige  Saize  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
54,.  189  (1845). 

3  B.  Tollens.  Handbuch  der  Praktischen  Medizin.  Ebstein-Schwalbe,  3,  pt.  2,  588 
(1901). 


56     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

The  Neutral  Urates.  —  The  neutral  urates  of  potassium  and 
sodium  were  first  prepared  by  Bensch.^  Uric  acid  was  warmed 
with  an  aqueous  sohition  of  the  base  free  from  carbonate  or 
carbon  dioxide,  and  then  precipitated  with  alcohol  or  evaporated 
down  in  an  atmosphere  free  from  carbonic  acid,  for  carbonic  acid 
decomposes  the  neutral  urate  to  acid  urate.  Bensch,  together 
with  Allen,^  prepared  also  the  neutral  salts  of  calcium,  barium, 
and  strontium,  and  determined  their  solubilities.  According  to 
these  authors,  neutral  potassium  urate  is  soluble  in  35  parts  of 
boiling  water  and  44  parts  of  cold  water,  neutral  sodium  urate 
in  77  parts  of  cold  water,  calcium  urate  in  1 ,440  parts  of  hot  water 
and  1,500  parts  of  cold  water,  barium  urate  in  2,700  parts  of  hot 
water  and  7,900  parts  of  cold  water,  and  strontium  urate  in  1,790 
parts  of  hot  water  and  4,300  parts  of  cold  water.  These  neutral 
salts  can  exist  only  in  a  solution  containing  some  of  the  free  base. 
The  view  expressed  by  Ebstein  ^  in  his  book  on  gout  that  the 
uric  acid  circulates  in  the  blood  as  neutral  urate  must  be  wrong, 
since  there  is  no  free  caustic  alkali  in  the  blood  and  there  is  plenty 
of  carbonic  acid  and  carbonates  which  would  decompose  the 
neutral  urates. 

The  Acid  Urates. — The  acid  urates  of  potassium,  sodium, 
ammonium,  calcium,  magnesium,  and  strontium  were  first  pre- 
pared and  their  solubilities  determined  by  Bensch.  Sodium  acid 
urate  is  soluble  in  122  parts  of  hot  water  and  1,150  of  cold  water, 
potassium  acid  urate  in  75  parts  of  hot  water  and  790  of  cold 
water,  ammonium  acid  urate  in  1,600  parts  of  boiling  water,  cal- 
cium acid  urate  in  276  parts  of  boiling  water  and  603  parts  of 
cold  water,  magnesium  acid  urate  in  160  parts  of  boiling  water 
and  3,750  parts  of  cold  water,  and  strontium  acid  urate  in  2,300 
parts  of  boiling  water  and  5,300  parts  of  cold  water.  The  acid 
urate  of  lithium  was  prepared  by  Schilling.^  He  found  it  soluble 
in  39  parts  of  boiling  water  and  370  parts  of  cold  water.  The 
acid  urates  of  potassium  and  sodium  can  be  prepared  by  treating 
the  neutral  urate  with  carbonates,  carbonic  acid,  or  acid  sodium 
phosphate,  or  by  dissolving  uric  acid  in  an  alkaline  carbonate. 

1  Bensch.  Ueber  einiger  Salze  der  Harnsaure.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
54,   189  (1845). 

Allen  iind  Bensch.  Ueber  die  neutralen  Salze  der  Harnsaure.  Liebig's  Ann.  der 
Chem.  u.  Pharm.,  65,  181  (1848). 

2  W.  Ebstein.     Die  Natur  und  Behandlung  der  Gicht,  98  (1882). 

3  V.  Schilling.  Ueber  die  Verbindung  der  Harnsaure  mit  Lithion.  Liebig's  Ann.  der 
Chem.  u.  Pharm.,  122,  241  (1862). 


Chemistry  57 

His  ^  studied  the  alkali  urates  with  considerable  care.  He 
found  that  if  sodium  hydroxide  be  gradually  added  to  a  solution 
of  uric  acid  containing  some  uric  acid  in  suspension,  sodium  acid 
urate  is  first  formed.  This  then  dissolves  on  addition  of  more 
sodium  hydrate,  forming  neutral  urate.  According  to  Pfeiffer,^ 
the  mono-basic  urates  react  neutral  and  not  acid  in  solution,  and 
only  in  the  presence  of  strong  alkalies  can  they  change  to  the 
soluble  dibasic  salt,  —  hence  tlie  uselessness  of  trying  to  dissolve 
the  gouty  concretions  of  acid  sodium  urate  with  weak  alkalies. 

The  acid  urates  exist  in  the  amorphous  form  and  in  the  form 
of  crystalline  needles.  If  acid  sodium  urate  is  precipitated  quickly 
from  solution  by  any  means,  it  comes  down  first  in  the  form  of 
little  balls.  These  are  the  ''  Kugelurates  "  ^  of  Mordhorst,  the 
"  Spharolithen  "  *  of  Ebstein  and  Nicolaier.  These  balls  soon 
begin  to  bristle  with  points  and  finally  change  to  needle-like 
crystals.  If  the  acid  urate  is  precipitated  slowly,  it  may  come 
down  crystalline  immediately. 

Baumgarten  ^  showed  by  analysis  that  the  amorphous  and  the 
crystalline  forms  of  the  acid  urate  have  the  same  chemical  com- 
position, and  that  as  soon  as  the  amorphous  form  is  washed  free 
from  impurities,  further  washing  with  pure  water  changes  it  to 
the  crystalline  form.  This  was  later  confirmed  by  Tunicliffe  and 
Rosenheim."  Mordhorst,^  who  studied  them  in  a  rough,  quali- 
tative way  only,  called  these  amorphous  balls  "  Kugelurates." 
He  thought  he  found  that  water  and  alcohol  dissolve  out  a  little 
alkali  from  them,  and  without  proof  assumed  that  they  had  a 
different  composition  from  the  crystalline  salt  and  from  uric  acid. 
He  believed  that  their  composition  is  variable,  that  the  amount 
of  base  in  them  depended  upon  the  concentration  of  the  base 

1  W.  His.  Physikalisch-chemische  Untersuchungen  iiber  des  Verhalten  der  Harnsaure 
und  ihrer  Salze  in  Losungen.  Verhandl.  des  18t  Kongr.  fiir  innere  Medizin,  Wiesbaden, 
425  (1900). 

2  E.  Pfeiffer.  Ueber  Harnsaureverbindungen  beim  Menschen.  Berl.  klin.  Wochenschrift, 
31,  913  (1894). 

3  Mordhorst.  Zur  Pathogenese  der  Gicht.  Verhandl.  des  14t  Kongr.  fiir  innere 
Medizin,  405  (1896).    Also 

Die  Entstehung  und  Auflosung  der  Harnsaureverbindungen  ausserhalb  und  innerhalb 
des  menschlichen  Korpers.     Zeitschr.  fiir  klin.  Medizin,  32,  65  (1897). 

*  W.  Ebstein  und  A.  Nicolaier.  Ueber  die  kunstliche  Darstellung  von  harnsiiuren 
Salzen  in  der  Form  von  Spharolithen.    Virehow's  Archiv  fur  path.  Anat.,  123,  373  (1891). 

5  Baumgarten.  Harnsaures  Natron  in  durchsichtigen  Kugelnerscheinend.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  117,  106  (1861). 

6  Tunicliffe  and  Rosenheim.  Contributions  to  our  Knowledge  of  Uric  Acid  Salts. 
Lancet,  1900,  1,  1708. 


58      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

in  the  solution  from  which  they  are  precipitated.  Ebstein  and 
Nicolaier  ^  found  that  they  show  a  black  cross  when  examined 
under  the  polarization  microscope. 

These  amorphous  urates  have  a  far  higher  solubility  than  the 
crystalline  forms.  Ord  ^  first  noticed  that  these  solutions  did  not 
act  altogether  like  real  solutions.  They  resemble  more  in  some 
ways  a  fine  suspension  in  water.  These  colloidal  solutions  were 
further  investigated  by  His,^  who  showed  that  the  acid  urate 
would  gradually  precipitate  out  on  standing,  appearing  first  as 
'*  Kugelurate  "  and  later  changing  to  the  crystalline  form.  The 
lithium  salt  shows  an  especially  great  tendency  to  form  super- 
saturated solution.  His  thinks  that  this  colloidal  form  may  play 
some  part  in  the  body.  Roberts  *  thinks  this  amorphous  form 
of  acid  urate  may  be  a  hydrate  of  sodium  acid  urate  and  calls 
attention  to  the  fact  that,  unlike  colloids,  generally  it  dializes. 
His  method  of  obtaining  this  form  of  the  salt  is  to  saturate  boiling 
water  with  sodium  acid  urate  and  then  cool.  On  cooling  the 
excess  of  acid  urate  does  not  separate  out,  but  if  we  add  common 
salt  to  the  solution,  it  then  precipitates  out  as  a  jelly,  which, 
on  standing,  slowly  becomes  crystalline.  The  precipitation  of 
the  amorphous  sodium  acid  urate  is  greatly  hastened  by  sodium 
salts  of  any  acid  and  also  by  uric  acid.  The  rapidity  of  precipi- 
tation seems  to  be  directly  dependent  on  the  concentration  of  the 
urate  or  the  uric  acid. 

Roberts  *  has  shown  that  when  blood  serum  or  a  solution  of 
sodium  salts  of  the  same  concentration  as  blood  serum  is  charged 
to  the  extent  of  one  part  to  about  5,000  to  6,000  with  amor- 
phous urate,  there  is  danger  of  precipitation.  Garrod  has  found 
this  amount  of  uric  acid  in  the  blood  at  times.  Roberts  further 
calls  attention  to  the  fact  that  urate  deposits  in  gout  occur  in 
the  parts  rich  in  sodium  salts.  According  to  him,  although  the 
blood  serum  and  the  lymph  are  rich  in  sodium  salts,  the  pre- 
cipitation of  acid  urate  would  be  less  likely  to  take  place  than 
in  the  synovial  fluid,  which  is  more  quiet.     The    reason  why  a 

1 W.  Ebstein  und  A.  Nicolaier.  Ueber  die  kunstliche  Darstellung  von  harnsauren 
Salzen  in  der  Form  von  Spharolithen.     Virchow's  Archiv  fiir  path.  Anat.,  123,  373  (1891). 

2  Ord.  On  the  Influence  of  Colloids  upon  the  Crystalline  Form  and  Cohesion.  London, 
1879,  72. 

3  W.  His.  PhysikaUsch-chemische  Untersuchungen  iiber  d.^s  Verhalten  der  Harnsaure 
und  ihre  Salze  in  Losungen.     Verhandl.  des  ISt  Kongr.  fiir  innere  Medizin,  425  (1900). 

■*  Sir  W.  Roberts.  Croonian  Lectures.  Chemistry  and  Therapeutics  of  Uric  Acid, 
Gravel,  and  Gout.     Lancet,  1892. 


Chemistry  59 

Blood  serum^ 0.70%  deposit    occurs  in  one  joint  and  not   in 

Lymph 0.70%  another  is  ascribed  by  him  to  the  varia- 

yno\ia ' ^^^  tions  in  the  composition  of  the  synovial 

Cartilage 0.90%  ^    •  •,     .  j-«-         /•    •    ^         t?       -x,    2    c    a 

Fibrous  tissue  ....  0.70%  ^^id  of  different  jomts.  Frenihs  finds 
Blood  corpuscles..  0.20%,  that  the  joints  of  resting  animals  con- 
Brain  0.20%  tain  more   synovial   fluid  than  those  of 

^^scle 0.08%  working  animals,  and  that  it  is  rich  in 

??''''^'' ^-^^^^      mineral    salts,    especially  sodium    salts. 

Liver  0.02%  ,         ,  .    , '        \   ,       ; 

This,  he  thinks,  might  have  some  con- 
nection with  the  fact  that  gouty  people  are  often  inactive. 
Dastre  and  Loye  ^  have  shown  that  the  concentration  of  the  blood 
in  NaCl  does  not  vary  much.  In  case  of  a  temporary  decrease 
in  the  amount  of  NaCl  in  the  food,  this  salt  is  extracted  from 
the  tissues  to  make  up  the  deficit.  In  case  the  salt  in  the  food 
is  especially  high,  it  is  temporarily  stored  up  in  the  synovia 
until  it  can  be  excreted  by  the  kidneys.  In  case  of  gout,  then, 
it  might  be  well  to  keep  the  common  salt  in  the  food  from  run- 
ning too  high,  according  to  Roberts,  who  says  that  mineral 
waters  high  in  sodium  salts  often  provoke  an  attack  of  gout 
almost  immediately  after  the  patient  begins  to  take  them. 

Ebstein  *  states  in  his  book  on  gout  that  neutral  sodium  urate 
circulates  in  the  blood,  and  that  this  under  the  influence  of  acid 
crystallizes  out  as  the  monosodium  urate  and  gives  the  gouty 
concretion.  This  cannot  be  true,  for  Pfeiffer  ^  has  shown  that 
monosodium  urate  can  form  only  in  an  alkaline  solution  and  that 
the  rate  of  formation  of  the  acid  sodium  urate  depends  on  the 
richness  of  the  solution  in  alkaline  salts.  Another  condition 
necessary  for  the  formation  of  acid  sodium  urate  is  the  presence 
of  carbon  dioxide  and  carbonates.  If  the  acid  salt  is  precipitated 
quickly  in  large  amounts,  the  "  Kugelurate."  is  thrown  down 
first  and  slowly  changes  to  the  crystalline  needle  form.  If  the 
precipitation  is  slow,  the  needles  are  formed  directly.  The  forma- 
tion of  this  salt  in  an  acid  solution,  as  well  as  its  further  existence 
in  such  a  solution,  is  impossible.  Acids  change  it  immediately  to 
its  components,  free  uric  acid  and  the  base.  This  salt  cannot, 
therefore,  come  down  from  acid  urine. 

1  Munk  and  Rosenstein.     Maly's  Jahresbericht,  Vol.  XX,  p.  40. 

2  Frenihs.     Wagner's  Handworterbuch  d.  Physiol.,  Vol.  Ill,  pt.  1,  p.  463. 

3  Dastre  et  Loye.     Lavage  du  Sang.     Archives  de  Physiologie,  1888,  p.  93. 
■•W.  Ebstein.     Die  Natur  und  Behandlung  der  Gicht,  1882. 

5  E.  Pfeiffer.  Ueber  Harnsaureverbindungen  beim  Alenschen.  Berl.  klin.  Wochen- 
schrift,  31,  913  (1894). 


60     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Roberts  ^  found  sodium  acid  urate  soluble  in  about  1 ,000  parts 
of  water,  but  in  10,000  parts  of  blood  serum.  He  found  that  if 
the  salts  are  dialized  out,  the  serum  then  dissolves  the  urate  as 
readily  as  pure  water.  In  an  aqueous  solution  of  the  blood-salts 
having  the  same  concentration  as  the  blood  itself,  the  acid  urate 
has  the  same  solubility  as  in  the  blood.  Sodium  chloride  and 
sodium  carbonate  are  the  chief  salts  of  the  blood,  and  Roberts 
found  that  an  aqueous  solution  of  these  of  the  same  strength  as 
found  in  the  blood  dissolves  just  as  much  uric  acid  as  the  blood 
serum.  He  showed  further  that  all  sodium  salts,  even  the  alka- 
line phosphate  and  carbonate  and  the  salicylate,  decrease  the 
solubility  of  the  acid  urate  enormously.  The  power  of  the 
different  salts  in  equi-molecular  solution  in  this  respect  is  about 
the  same.  Potassium  salts  have  no  effect  on  the  solubility  of  the 
acid  urate  of  sodium.  Magnesium,  calcium,  and  ammonium  salts 
decrease  the  solubility  of  the  urate.  Experiments  with  the  carbon- 
ate of  potassium  and  lithium  showed  that  these  and  also  piperazin 
do  not  make  sodium  acid  urate  any  more  soluble  in  blood  serum. 

A  priori  we  should  expect  that  the  solubility  of  sodium  acid 
urate  in  salt  solutions  would  be  just  as  Roberts  showed.  His  ^ 
has  explained  the  facts  from  the  laws  of  electrolytic  dissociation. 
In  the  same  manner  that  acids,  by  increasing  the  concentration 
of  the  hydrogen  ions  in  a  solution,  decrease  the  dissociation  and 
therefore  the  solubility  of  uric  acid,  so  sodium  salts,  by  increasing 
the  concentration  of  the  sodium  ions,  decrease  the  dissociation 
and  therefore  the  solubility  of  the  sodium  acid  urate. 

Sodium  acid  urate  in  solution  is  partly  dissociated  into  the 

positive  sodium  ion  and  the  negative  uric  acid  ion  C5N3H3O3,  and 

the  relation  between  them  and  the  undissociated  portion  of  the 

PXN 
urate  is  determined  by  the  equation  — z^ —  ^  ^  where  P  stands 

for  the  concentration  of  the  positive  ion  Na,  N  for  the  con- 
centration of  the  negative  uric  acid  ion  C5N3H3O3 ,  and  U  for 
the  concentration  of  the  undissociated  portion  of  the  urate.  In 
a  saturated  solution  U  is  a  constant,  and  the  equation  becomes 
P  X  N  =  KU,  where  KU  is  a  constant.     If  we  add  a  sodium  salt, 

1 W.  Roberts.  On  the  History  of  the  Uric  Acid  in  the  Urine.  Medico-Chirurgical 
Transactions,  73,  245  (1890). 

2  W.  His.  PhysikaUsch-chemische  Untersuchungen  iiber  das  Verhalten  der  Harnsaure 
und  ihrer  Salze  in  Losnngen.  Verhandl.  des  18t  Kongr.  fiir  innere  Medizin,  Wiesbaden, 
425  (1900). 


Chemistry  61 

for  example,  NaCl  or  NajCOg,  the  increase  in  the  concentration 
of  the  sodium  ion  P  will  cause  a  decrease  in  N,  the  concentrations 
of  the  negative  uric  acid  ion,  in  order  that  the  product  P  X  N 
remain  constant.  In  other  words,  if  a  sodium  salt  be  added  to  a 
saturated  solution  of  sodium  acid  urate,  we  should  expect,  theo- 
retically, a  decrease  in  the  concentration  of  the  dissociated  urate, 
and,  since  in  a  saturated  solution  at  any  given  temperature  the 
concentration  of  the  vmdissociated  portion  of  the  uric  acid  is  a 
constant,  a  decrease  in  the  concentration  of  the  undissociated 
urate  means  a  decrease  in  the  solubility  of  the  salt  itself.  As 
we  have  seen,  Roberts  showed  that  sodium  salts  do  decrease 
enormously  the  solubility  of  sodium  acid  urate.  A  solution  of 
common  salt  of  so  low  a  concentration  as  0.7  per  cent  decreases 
the  solubility  of  sodium  acid  urate  to  about  one  tenth  its  value  in 
pure  water.  Since  all  sodium  salts  have  this  action  it  is  useless 
to  attempt  tc>  dissolve  gouty  concretions  by  administration  of 
bicarbonate  of  soda.  In  this  connection  it  might  also  be  men- 
tioned that  Jones  found  by  experiment  that  ammonium  salts  in 
the  same  way  lessen  the  solubility  of  ammonium  urate  and  precipi- 
tate it  from  solution.^ 

Vicario  ^  has  studied  the  solubility  of  a  number  of  the  more 
soluble  salts  of  uric  acid,  and  gives  the  following  results: 

Grams  of  Salt 

100  cc.  of  water  dissolves                                                        at  18°  at  37° 

Acid  sodium  urate 0.088  0.172 

Neutral  sodium  urate 1.695  2.806 

Acid  potassium  urate    0.150  0.290 

Neutralfpotassium  urate 2.320  2.553 

Acid  lithium  urate 0.258  0.276 

Neutral  lithium  urate   .  .  .  '. 1.505  2.055 

Acid  calcium  urate    0.175  0.205 

Neutral  calcium  urate 0.070  0.065 

Propylamin  urate 0.285  0.426 

Ethylendiamin  urate 0.520  0.705 

Urotropin  urate 0.633  2.200 

Piperazin  urate 2.223  2.270 

Lysidin  urate 4.195  5.663 

Dimethylpiperazin  urate 5.370  6.086 

Since  the  solubility  of  sodium  acid  urate  is  only  one  part  in 
about  1,000,  the  salts  of  potassium,  lithium,  piperazin,  etc.,  have 

1  H.  B.  Jones.     On  the  State  in  which  Uric  Acid  Exists  in  the  Urine.     Lancet,  1843,  366. 

2  A.  Vicario.     De   la   valeur   compar^e   des   principaux  dissolvants   de  I'acide   urique. 
Journ.  Pharm.  Chim.,  6,  15,  265  (1902). 


62      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

been  administered  in  the  hope  of  making  gouty  concretions  more 
soluble.  The  uselessness  of  this  plan  can  be  seen  from  the  follow- 
ing considerations:  A  saturated  solution  of  sodium  acid  urate 
to  which  has  been  added  a  lithium  salt,  for  example  LiCl,  contains 
the  positive  ions  Na  and  Li,  and  the  negative  ions  CI  and  C5H3N3O3 
with  also  a  very  little  of  the  undissociated  salts.  The  solubility 
constant  K  for  the  sodium  acid  urate  is  the  same  in  this  ease 
as  when  there  is  nothing  but  sodium  acid  urate  present,  and  in  a 
saturated  solution  we  have  P  X  N  =  KU  (a  constant).  N,  that 
is,  the  concentration  of  the  dissociated  uric  acid,  and  that  means 
practically  the  solubility  of  the  uric  acid,  since  in  such  a  dilute 
solution  of  urates  the  dissociation  is  practically  complete,  cannot 
increase,  for  immediately  P  would  have  to  decrease  and  sodium 
acid  urate  would  crystallize  out.  In  other  words,  the  presence 
of  the  lithium  does  not  enable  more  uric  acid  to  remain  in  solu- 
tion. This  again  agrees  with  the  experimental  evidence  of 
Roberts  that  potassium  and  lithium  salts  do  not  increase  the 
solubility  of  the  sodium  acid  urate.  In  other  words,  the  solu- 
bility of  the  urates  is  determined  by  the  solubility  of  the  least 
soluble  urate  present.  From  this  we  should  expect  that  salts  of 
calcium,  magnesium,  and  barium,  whose  urates  are  less  soluble 
than  that  of  sodium,  would  decrease  the  solubility  of  mono- 
sodium  urate,  and  again  Roberts  showed  that  this  is  the  case. 
It  has,  in  fact,  been  shown  that  even  very  large  doses  of  potassium 
and  lithium  salts  do  not  increase  the  excretion  of  uric  acid  in  gout. 
Piperazin,  which  forms  a  salt  with  uric  acid  soluble  in  50  parts 
of  pure  water ,^  does  not  dissolve  uric  acid  in  the  urine. ^  The 
same  is  true  of  lysidin,  which  forms  a  salt  soluble  in  6  parts  of  pure 
water. 

Carbonic  acid  causes  uric  acid  to  precipitate  from  a  solution  of 
monosodium  urate.  In  a  solution  of  sodium  acid  urate  to  which 
carbon  dioxide  has  been  added,  we  have  among  other  things  some 
negative  uric  acid  ions  from  the  dissociated  urate,  and  some 
hydrogen  ions  from  the  carbonic  acid.  Carbon  dioxide  in  solu- 
tion forms  carbonic  acid,  HjCOg,  and  this  dissociates  in  part  to 

1  Biesenthal  und  Schmidt.  Piperazin  bei  Gicht-  und  Steinleiden.  Berl.  klin.  Wochen- 
schrift,  28,   1214  (1891). 

2  Mendelsohn.  Ueber  Harnsaxirelosung  insbesonderer  durch  Piperazin.  Berl.  klin 
Wochenschrift,  29,  884  (1892). 

M.  Mendelsohn.  Die  Verschiedenheit  des  Problems  der  Harnsaureauflosung  bei  gieht- 
isehen  Ablagerungen  und  bei  Konkretionem  in  den  Harnwegen.  Deutsche  Med.  Wochen- 
schrift, 21,  283  (1895). 


Chemistry  63 

the  positive  H  ion  and  the  negative  CO3  ion.  When  the  concen- 
tration of  the  hydrogen  ions  is  great  enough  to  give  with  the  nega- 
tive uric  acid  ions  a  product  which  reaches  the  value  KU  in  the 
equation  P  X  N  =  KU,  uric  acid  begins  to  precipitate  out.  The 
precipitation  of  monosodium  urate  from  a  solution  of  the  neutral 
urate  can  be  explained  in  a  somewhat  similar  way. 

The  Quadri urate.  — The  question  of  the  existence  of  a  third 
kind  of  urate,  the  so-called  quadriurate  or  hemiurate,  containing 
half  as  much  of  the  base  as  the  acid  urate,  that  is,  one  atom  of  the 
base  to  two  molecules  of  uric  acid,  is  somewhat  connected  with 
the  question  of  the  composition  of  the  amorphous  urate  deposit 
in  urine.  It  was  the  study  of  this  amorphous  deposit  which  first 
led  to  the  belief  that  a  third  kind  of  urate  exists. 

Berzelius,^  the  first  who  mentions  the  subject,  thought  that 
the  uric  acid  in  the  urine  existed  in  the  free  condition.  He  no- 
ticed the  formation  of  uric  acid  crystals  on  treatment  of  the  sedi- 
ment with  water.  Lehmann  ^  later  identified  these  crystals  as 
free  uric  acid. 

Proust,^  one  of  the  first  writers  on  the  subject,  at  first  thought 
the  deposit  a  real  acid,  which  he  called  "  acide  rosacique."  Later, 
he  believed  th^t  it  was  uric  acid  contaminated  with  coloring 
matter.  Prout  ^  believed  it  to  be  ammonium  urate,  and  said 
that  uric  acid  is  dissolved  in  urine  as  ammonium  urate.  Donne 
agreed  with  Prout.  Quevenne  *  believed  it  to  be  either  a  hydrate 
of  uric  acid  or  a  compound  of  uric  acid  with  coloring  matter  and 
contaminated  with  a  little  ammonia.  Wetzlar  ^  and  Schultens,^ 
without  any  proof,  believed  it  was  sodium  urate.  Duvernoy  ^ 
said  it  was  not  ammonium  urate,  but  uric  acid  contaminated  with 
coloring  matter.  He  ascribed  to  the  coloring  matter  the  property 
of  holding  uric  acid  in  solution,  and  thought  the  precipitation  was 
due  to  a  change  in  the  composition  of  the  coloring  matter.  But 
Prout,  in  his  book  just  mentioned,  shows  that  the  colorless  ser- 
pent excrement  is  as  soluble  as  the  urine  deposit,  so  that  Duver- 

1  Berzelius.     Lehrbuch  der  Chemie. 

2  Lehmann.     Lehrbuch  des  physiologische  Chem.,  Vol.  II,  p.  355. 

3  Prout.  On  the  Nature  and  Treatment  of  Stomach  and  Renal  Diseases.  London, 
1843,  p.  188. 

*  L'Heritier.     Chimie  pathologique,    1842. 

'  Wetzlar.  Beitrage  zur  Kenntniss  des  menschlichen  Ham  und  der  Entstehung  der 
Harnsteine. 

*  Schultens.     Neues  Journal  der  Chemie,  Vol.  Ill,  p.  347. 

''  Duvernoy.  Chemische-medicinische  Untersuchungen  viber  den  menschlichen  Urin, 
1835,  p.  20. 


64     The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

noy's  view  must  be  wrong.  Willis  ^  said  that  the  solubility  of 
uric  acid  in  urine  is  due  to  the  formation  of  a  soluble  hydrate, 
but  Fritzsch  has  shown  that  on  adding  acid  to  a  urate  it  is  the 
hydrate  of  uric  acid  which  first  precipitates,  so  that  the  hydrate 
is  insoluble.  Becquerel  ^  agreed  with  Quevenne,  and  thought 
that  the  deposit  is  uric  acid  with  impurities  of  coloring  matter 
and  perhaps  a  little  ammonium  salt. 

Scherer  ^  said  that  the  uric  acid  is  in  the  urine  as  sodium  urate, 
and  that  the  deposit  is  uric  acid  set  free  by  lactic  acid.  Lipowitz  ^ 
agreed  with  Scherer.  Liebig  and  Heintz  *  showed  that  the  urine 
does  not  normally  contain  any  lactic  acid,  so  that  both  Scherer 
and  Lipowitz  are  wrong. 

Heintz  ^  showed  the  presence  of  potassium,  sodium,  ammonium, 
and  often  calcium  and  magnesium,  in  the  red  amorphous  urine 
deposit.  He  noticed  that  there  is  considerably  more  uric  acid 
in  the  deposit  than  can  be  accounted  for  by  assuming  that  it  is 
all  united  with  the  bases  in  the  form  of  acid  urate,  and  succeeded 
in  obtaining  a  body  or  mixture  of  bodies  which  correspqnded 
somewhat  with  a  quadriurate  formula,  that  is,  contained  half  as 
much  base  as  the  acid  urate. 

Von  Scherer  ^  said  that  in  the  amorphous  urine  sediment  there 
is  no  crystalline  uric  acid,  but  there  is  sodium,  and  also  more  uric 
acid  than  can  be  accounted  for  by  assuming  that  it  is  all  com- 
bined as  acid  urate.  He  did  get  sediments  in  which  the  excess 
of  uric  acid  over  that  necessary  to  form  urate  was  somewhere  near 
half  the  total  uric  acid.  But  he  called  attention  to  the  fact  that 
amorphous  urine  sediment  and  the  sediment  obtained  by  mix- 
ing acid  urate  and  neutral  phosphate  of  soda  always  contains 
some  sodium  phosphate,  no  matter  how  much  we  may  attempt 
to  purify.  He  says  that  the  amount  of  sodium  in  the  deposit, 
depends  on  the  amount  of  acid  sodium  phosphate  in  the  urine, 
and  thinks  that  the  sediment  is  a  mixture  of  uric  acid  and  acid 
sodium  urate.     His  artificial  deposit  is  obtained  by  adding  uric 

1  Willis.     Krankheiten  des  Harnsystems,  1841,  p.  20. 

2  Becquerel.     Semiotiques  des  urines,  1841,  p.  45. 

3  I^ipowitz.  Simon's  Beitrage  zur  physiologische  und  patliologische  Chemie  und  Mikro- 
skopie,  1,  97. 

*  Liebig  und  Heintz.  Ueber  eine  neue  Saure  im  nienschlichen  Harn.  Poggendorf 's 
Annal.,  62,  602  (1844). 

5  W.  Heintz.  Ueber  die  Harnsauren  Sedimente.  MuUer's  Arch,  fiir  Anat.  Physiol. 
und  Wissenschaftl.  Medizin,  1845,  30. 

Ueber  die  harnsauren  Sedimente.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  45,  55  (1845). 

*  Von  Scherer.     Jahresbericht  iiber  die  Fortschritte  in  der  Biologie,  1845,  156. 


Chemistry  65 

acid  to  a  warm  solution  of  disodium  phosphate  which  has  been 
made  nearly  neutral  with  phosphoric  acid  and  then  cooling. 
This  is  the  method  used  by  later  experimenters  to  obtain  arti- 
ficial urine  sediment.  It  gives  a  precipitate  which  resembles 
the  urinary  deposit  very  much. 

Jones  was  the  next  to  study  the  urinary  sediment.  At  first  ^ 
he  believed  it  to  be  ammonium  urate.  Later  ^  he  took  another 
view.  He  worked  mostly  with  sediment  prepared  artificially 
from  disodium  urate  and  uric  acid.  He  noticed  that  no  uric 
acid  crystals  can  in  most  cases  be  found  in  the  amorphous  sedi- 
ment, that  there  is  considerably  more  uric  acid  in  the  sediment 
than  can  be  accounted  for  by  assuming  that  it  is  all  combined 
as  biurate,  and  that  on  treating  the  sediment  with  distilled 
water  after  washing  out  impurities,  some  uric  acid  crystals  are 
formed. 

From  the  amount  of  sodium  and  the  total  amount  of  uric  acid 
found  by  Scherer  in  his  analyses,  Jones  calculated  the  ratio  be- 
tween the  amount  of  uric  acid  in  each  case  needed  by  the  sodium 
to  form  acid  urate  and  the  excess  of  uric  acid  in  the  sediment,  and 
found  this  to  be  in  four  cases,  respectively,  1 : 2.04,  1 : 0.17,  1 : 0.42, 
and  1:2.08.  This  gives  an  average  of  1:1.18.  Jones  himself 
prepared  a  few  sediments  and  found  this  ratio  in  three  cases  to  be : 
1 : 1.72, 1 : 0.46,  and  1 : 1.04.  These  ratios  give  an  average  of  1 : 1.07. 
He  assumed  that  the  averages  of  these  two  sets  of  results  were 
near  enough  to  each  other  and  near  enough  to  the  ratio  of  1 : 1  to 
be  called  1:1.  Many  of  his  sediments  gave  discordant  results. 
In  some  cases  the  sediment  seemed  to  be  practically  all  uric  acid  ; 
in  other  cases  it  nearly  all  dissolved  and  only  contained  enough 
uric  acid  to  combine  with  the  sodium  as  acid  urate.  Such  cases, 
however,  he  rejected  as  faulty  in  his  calculations.  From  all 
these  facts  he  assumed  that  there  is  sometimes  in  urinary  sedi- 
ment a  body  whose  formula  may  be  written  NaC5H3N^03  + 
C5H4N4O3.  This,  he  said,  is  an  unstable  body,  easily  decomposed 
by  water  into  uric  acid  and  sodium  acid  urate. 

Jones  had  no  right  to  assume  that  there  is  a  chemical  compound 
that  contains  half  as  much  sodium  as  the  monosodium  urate. 
In  the  first  place,  on  account  of  the  fact  that  under  the  micro- 

1  H.  B.  Jones.  On  the  State  in  which  the  Uric  Acid  Exists  in  the  Urine.  Medico- 
Chirurgical  Transactions,  1844,  102. 

2  Ibid.  On  the  Composition  of  the  Amorphous  Deposit  of  Urates  in  Healthy  Urine. 
Journ.  of  the  Chem.  Soc,  London,  1862,  201. 


66      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

scope  he  could  not  see  any  crystals  of  uric  acid,  he  said  that  there 
is  no  free  uric  acid  in  the  sediment.  But  Fritzsch,^  Matignon,^ 
and  His  ^  have  shown  that  uric  acid  can  exist  in  the  amorphous 
form,  a  form  in  which  condition,  of  course,  Jones  could  not  recog- 
nize it  under  the  microscope.  These  same  authors  have  likewise 
shown  that  the  amorphous  uric  acid  becomes  crystalline  on  stand- 
ing in  water,  just  what  happened  in  the  work  of  Scherer  and 
Jones.  Jones  thought,  however,  that  this  formation  of  crystals 
w^as  due  to  the  appearance  of  uric  acid  set  free  from  the  quadri- 
urate.  In  the  next  place,  the  ratios  between  the  uric  acid  neces- 
sary to  combine  with  the  sodium  in  the  sediment  and  the  excess 
are  so  discordant  that  an  average  means  absolutely  nothing. 
Besides,  their  method  of  determining  uric  acid  by  precipitation 
with  HCl  has  been  shown  to  be  very  much  in  error.  Again,  their 
ratio  in  any  case  was  not  1:1.0  or  anywhere  near  it.  Further, 
Scherer  showed  that  the  sediment  always  contains  sodium  phos- 
phate, and  finally,  Jones  threw  out,  without  any  right  to  do  so, 
those  of  his  experiments  in  which  the  ratio  between  the  combined 
and  the  free  uric  acid  did  not  agree  well  with  his  theory. 

Roberts,*  in  1890,  made  a  study  of  the  natural  and  artificial 
urinary  sediments,  and  later  elaborated  the  results  of  the  work 
in  his  Croonian  ^  lectures.  He  agreed  with  Jones  that  salts  of 
uric  acid  containing  half  as  much  of  the  base  as  the  biurate 
and  easily  decomposed  by  water  exist.  He  went  further  and 
stated  that  the  quadriurate  of  sodium  is  the  form  in  which  the 
uric  acid  exists  in  the  urine  and  in  the  blood. 

Roberts  reviewed  the  work  of  Jones  without,  however,  the 
proper  criticism,  and  then  by  a  few  experiments  showed  that  the 
excrement  of  birds  and  reptiles  was  similar  to  the  amorphous 
sediment  of  human  urine.  This  sediment,  on  treatment  with 
a  large  quantity  of  water,  gives  uric  acid  crystals  and  also 
sodium  biurate.  The  sodium  biurate  goes  into  solution.  He 
found  the  sediment  so  impure,  however,  that  the  quantitative 

1  Fritzsch.  Verbindung  von  Harnsaure  mit  Schwefelsaure.  Liebig's  Ann.  der  Chent. 
u.  Pharm.,  28,  332  (1838). 

2  M.  Matignon.     Sur  I'hydrate  d'acide  urique.     Bull,  de  la  Soc.  Chim.  (3),  11,  571  (1894). 

3  W.  His.  Physikalisch-chemische  Untersuchungen  iiber  das  Verhalten  der  Harnsaure 
und  ihrer  Salze  in  Losungen.  Verhandl.  des  ISt  Kongr.  ftir  innere  Medizin,  425 
(1900). 

*W.  Roberts.  On  the  History  of  the  Uric  Acid  in  the  Urine.  Medico -Chirurgical 
Transactions,  Vol.  LXXIII,  245  (1890). 

5  Ihid.  Chemistry  and  Therapeutics  of  Uric  Acid  Gravel  and  Gout.  (Croonian 
Lectures.)     Lancet,  1892. 


Chemistry  67 

relations  between  the  sodium  and  the  uric  acid  were  never  such 
that  he  could  assume  that  the  c^uadriurate  was  certainly  present. 
He,  therefore,  prepared  artificial  sediment  by  treating  a  solution 
of  uric  acid  in  sodium  hydroxide  with  acetic  acid.  By  this  method 
he  obtained  a  granular  precipitate  which  looked  somewhat  similar 
to  ordinary  amorphous  urinary  sediment,  but  which  was  color- 
less. He  washed  it  a  little  with  alcohol,  and  then  treated  it  with 
a  large  quantity  of  distilled  water.  After  a  while,  the  water 
extracted  from  the  sediment  sodium  acid  urate  and  left  behind 
crystalline  uric  acid.  The  amount  of  crystalline  uric  acid  and 
also  the  amount  of  uric  acid  which  went  into  solution  was  deter- 
mined by  precipitation  with  acid,  and  the  ratio  of  the  former 
to  the  latter  was  found  in  two  cases  to  be  as  1: 1.27  and  1: 1.12, 
respectively.  He  then  made  a  number  of  analyses  of  artificial 
sediments  obtained  by  this  and  other  methods  and  found  that 
the  amount  of  acid  and  alkali  in  the  solution  has  to  be  very  care- 
fully adjusted  in  order  to  get  a  sediment  the  composition  of  which 
corresponds  to  a  quadriurate  formula.  If  the  solution  were  too 
strongly  acid,  he  obtained  a  sediment  which  contained  too  much 
uric  acid.  If  the  solution  were  too  strongly  alkaline,  the  sedi- 
ment contained  too  little  uric  acid. 

By  carefully  selecting  pieces  of  bird's  urine  he  succeeded  in 
getting  a  couple  of  samples  in  which  the  ratio  of  the  combined 
uric  acid  and  the  free  was  within  a  few  per  cent  of  1:1.  With 
serpent's  urine  he  could  not  find  any  such  ratio. 

E.  Pfeiffer^  showed  that  the  sediment  obtained  by  Roberts' 
method  always  contains  phosphate  of  sodium  even  after  repeated 
w^ashing  and  even  after  the  final  alcoholic  or  aqueous  washing 
appears  to  be  free  from  phosphate.  He  showed  that  if  an  arti- 
ficial precipitate  is  obtained  by  Roberts'  method,  —  precipitation 
from  sodium  phosphate  solution,  —  it  contains  sodium,  phosphoric 
acid,  and  uric  acid,  and  according  to  the  reaction  of  the  solution 
there  is  obtained  a  sediment  rich  in  sodium  and  phosphate  acid 
and  poor  in  uric  acid,  or  the  reverse,  or  a  sediment  containing 
sodium  and  uric  acid  in  any  of  the  intermediate  ratios.  When 
a  precipitate  is  obtained  which  contains  sodium  and  uric  acid  in 
the  proportion  to  form  a  quadriurate,  it  is  due  to  accident  or  to 
careful  adjustment  of  the  conditions.     He  calls  attention  to  the 

^  E.  Pfeiffer.  Ueber  Harnsaureverbindungen  beim  Menschen.  Berl.  klin.  Wochen- 
schrift,  31,  913  (1S94). 


68     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

fact  that  neither  Jones  nor  Roberts  found  any  quadriiirate  in 
natural   urinary  sediment. 

Warnecke  ^  has  recently  reaffirmed  what  has  been  known  for 
thirty  years,  that  Heinze's  method  for  the  determination  of  uric 
acid,  the  method  used  by  Jones  and  also  by  Roberts,  is  very  far 
from  accurate. 

Again,  in  treating  the  sediment  with  water  to  decompose  the 
quadriurate  and  dissolve  out  the  acid  urate,  nearly  six  per  cent 
of  the  free  uric  acid  is  dissolved.  Roberts  corrects  for  this,  but 
does  not  take  it  into  account  when  he  determines  the  combined 
uric  acid  in  the  solution. 

Besides  this  large  error,  there  is  another  due  to  the  fact  that 
in  his  determination  of  uric  acid,  Roberts  dried  it  at  a  temperature 
of  37°.  Tunicliffe  and  Rosenheim  ^  have  shown  that  a  large 
amount  of  water  is  still  retained  by  the  acid  after  heating  at  this 
temperature.  These  authors  confirm  the  view  of  Pfeiffer^  that 
in  the  artificial  sediment  the  ratio  between  the  free  and  the  com- 
bined uric  acid  is  very  variable.  They  say  that  the  sediment  is 
a  mixture  of  sodium  acid  urate,  uric  acid,  and  water.  A  mixture 
of  amorphous  uric  acid  with  amorphous  acid  urate  was  shown 
by  them  to  act  like  the  so-called  quadriurate  sediment.  The 
urate  went  into  solution  and  the  uric  acid  became  crystalline. 

There  seems  no  question,  then,  that  the  so-called  quadriurates 
are  mixtures  of  acid  urate  with  varying  amounts  of  uric  acid. 
On  treatment  with  large  quantities  of  water,  the  acid  urate  goes 
into  solution  and  the  amorphous  uric  acid  becomes  crystalline. 
This  is  what  happens  when  either  of  these  bodies  alone  is  treated 
with  water,  or  when  a  mixture  of  the  two  is  so  treated. 

His  ^  has  explained  the  precipitation  of  the  mixture  of  uric 
acid  and  acid  urate.  On  addition  of  carbonic  acid  to  a  solution 
of  urate,  as  we  have  seen,  the  acid  urate  first  precipitates,  on 
account  of  the  solution  becoming  saturated  with  it.  On  further 
addition  of  carbonic  acid,  when  the  product  of  the  negative  uric 
acid  ions  and  the  hydrogen  ions  from  the  carbonic  acid  reaches 

1  Warnecke.     Dissertation,   Gottingen,   1898. 

2  Tunicliffe  and  Rosenheim.  Contributions  to  our  Knowledge  of  Uric  Acid  Salts. 
Lancet  (1900),  1,  1708. 

3  E.  Pfeiffer.  Ueber  Harnsaureverbindungen  beim  Menschen.  Berl.  klin.  Wochen- 
schrift,  31,  913  (1894). 

*  W.  His.  Physikalisch-chemische  Untersuchungen  liber  das  Verhalten  der  Harnsaure 
und  ihrer  Salze  in  Losungen.  Verhandl.  des  18t  Kongr.  fur  innere  Medizia,  Wiesbaden , 
1900,  425. 


Chemistry  69 

the  value  of  the  solubihty  constant  for  uric  acid,  then  free  uric 
acid   precipitates. 

Compounds  of  Uric  Acid  with  Urea  and  Kreatin.  —  Riidel  ^ 
states  that  the  presence  of  urea  increases  the  solubihty  of  uric 
acid  in  water  or  in  urine,  and  that  the  uric  acid  from  this  com- 
pound, unlike  the  uric  acid  in  urates,  is  not  easily  precipitated 
with  acids.  His  experiments  seem  to  show  this.  He  prepared 
a  body  which  on  analysis  gave  results  that  approximated  the 
formula  C5H4N4O3  +  CO(NH2)2  ^-  HjO,  a  compound  of  one  mole- 
cule of  uric  acid,  one  molecule  of  urea  and  one  molecule  of 
water  of  crystallization.  In  the  same  article  he  reached  the 
conclusion  that  uric  acid  is  more  soluble  in  dilute  HCl  than  in 
water.  The  latter  conclusion  has  been  shown  theoretically  not 
probable,  and,  in  fact,  certainly  experimentally  wrong,  by  His.^ 
Neither  His^  nor  Klemperer^  could  confirm  the  existence  of  a 
compound  of  uric  acid  and  urea,  and  His  ^  found  that  urea  does 
not  increase  the  solubility  of  uric  acid  in  water.  From  the 
work  of  Riidel  it  has  been  assumed  by  many  physicians  that 
urea  increases  the  solubility  of  uric  acid  in  blood  likewise,  and 
a  large  meat  diet  has  therefore  been  recommended  by  these 
men  in  gout.  It  has  even  been  suggested  to  give  10  to  15  grams 
of  pure  urea.  The  work  of  His  ^  and  Klemperer  ^  has  shown  that 
there  is  no  basis  for  this.  Klemperer  found  that  kreatin  forms 
a  compound  with  uric  acid,  but  His"*  has  shown  that  this  is 
merely  an  ordinary  salt  decomposed  by  acids  like  the  salt  of 
piperazin  and  uric  acid. 

Compounds  of  Uric  Acid  with  Nucleic  and  Thymic  Acids 
and  Formaldehyde.  —  KosseP  showed  that  nucleic  acid  com- 
bines with  the  purin  bases  and  forms  a  soluble  body  from  which 
ammoniacal  silver  nitrate  solution  does  not  precipitate  the  base. 
Kossel  and  Neumann  ^  showed  that  thymic  acid  acts  in  the  same 

1  Riidel.  Zur  Kenntniss  der  Losungsbedingungen  der  Harnsaure  in  Harn.  Arch, 
fiir  exp.  Path.  u.  Pharm.,  30,  469  (1892). 

2  W.  His.  Physikalisch-chemische  Untersuchungen  iiber  das  Verhalten  der  Harnsaure 
und  ihrer  Salze  in  Losungen.  Verhandl.  des  18t  Kongr.  fiir  innere  Medizin,  Wiesbaden, 
1900,  425. 

3  Klemperer.  Harnsaure  Kreatinin  eine  wasserlosUch  Harnsaureverbindungen.  Fort- 
schritte  Mediz.,  19,  328. 

*  W.  His.  Die  Harnsiiureablagerungen  des  Korpers  und  die  Mittel  zu  ihrer  Losung. 
Therapie  der  Gegenwart,  Neue  Folge,  3,  434  (1901). 

^  Kossel.     Du  Bois  Reymond's  Archiv  fiir  Physiologie,  1893.     Remark. 

6  A.  Kossel  und  A.  Neumann.  Ueber  Nucleinsaure  und  Thyminsiiure.  Zeitschr.  fiir 
physiol.  Chem.,  22,  81  (1896). 


70     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

way.  This  led  Goto  ^  to  study  the  action  of  nucleic  and  thymic 
acids  on  uric  acid.  If  we  add  the  sodium  salt  of  thymic  acid  to  a 
solution  of  uric  acid  in  sodium  hydroxide,  and  then  acidify  the 
solution  with  HCl,  a  large  amount  of  uric  acid  stays  in  solution 
even  on  standing  a  couple  of  days.  From  a  similar  solution 
containing  no  thymic  acid,  the  HCl  precipitates  all  but  a  small 
fraction  of  the  uric  acid.  We  know  that  carbon  dioxide  pre- 
cipitates sodium  acid  urate  from  a  solution  of  uric  acid  in  sodium 
hydrate.  But  if  we  add  some  of  the  sodium  salt  of  thymic  acid 
to  a  solution  of  neutral  sodium  urate  and  then  attempt  to  precipi- 
tate sodium  acid  urate  with  carbon  dioxide  we  find  that  an 
exceedingly  large  amount  of  sodium  acid  urate  stays  in  solution. 
In  other  words,  we  find  that  nucleic  acid  and  thymic  acid  increase 
the  solubility  of  sodium  acid  urate  in  water,  and  that  acids  do 
not  precipitate  the  uric  acid  from  the  solutions.  In  a  remark 
after  the  paper  of  His,^  Minkowski  stated  that  he  had  prepared 
independently  a  soluble  compound  of  nucleic  acid  and  uric  acid 
and  suggested  that  this  may  be  the  combination  in  which  uric 
acid  circulates  in  the  blood.  He  stated  that  he  might  publish 
the  details  of  his  work  later,  but  I  cannot  find  that  he  has  done 
so. 

Goto  did  but  a  few  experiments  and  the  differences  in  solubility 
in  the  presence  and  in  the  absence  of  thymic  and  nucleic  acids 
were  not  very  large.  Further,  in  some  of  the  experiments,  uric 
acid  seemed  to  precipitate  gradually  on  standing  even  in  the 
presence  of  the  nucleic  and  thymic  acids. 

His  ^  has  prepared  a  similar  soluble  compound  of  formaldehyde 
and  uric  acid  from  which  the  uric  acid  is  not  precipitated  by  acids, 
and  he  believes  that  there  may  well  be  a  large  number  of  bodies 
which  combine  similarly  with  uric  acid,  among  which  we  may 
find  a  body  which  will  be  of  therapeutic  value  in  dissolving 
uric  acid.     Urotropin  which  decomposes  in  the  body  and  gives 

1  Kossel  und  Goto.  Sitzungberichte  der  Gesellschaft  zur  Beforderung  der  Natiirwissen- 
schaften.     Marbung,  1900.    Also 

M.  Goto.  Ueber  die  Losung  der  Harnsaure  diirch  Nucleinsaure  und  Thjoninsaure. 
Zeitschr.  fiir  physiol.  Ghem.,  30,  473  (1900). 

2  W.  His.  Physikalisch-chemische  Untersuchungen  iiber  das  Verhalten  der  Harn- 
saure und  ihrer  Salze  in  Losungen.  Verhandl.  des  ISt  Kongr.  fiir  innere  Medizin, 
Wiesbaden,  1900,  425. 

2  Ibid.  Die  Harnsaureablagerungen  des  Korpers  und  die  Mittel  zu  ihrer  Losung. 
Therapie  der  Gegenwart,  Neue  Folge,  3,  434  (1901). 


Chemistry  71 

formaldehyde  which  combines  with  m-ic  acid  was  introduced  as 
a  therapeutic  agent  by  Nicolaier.^ 

Uric  Acid  in  the  Urine 

The  behavior  of  the  uric  acid  in  the  urine  has  not  previously 
been  fully  explained.  The  laws  of  physical  chemistry,  however, 
give  us  a  full  explanation  of  the  precipitation  of  uric  acid  when 
urine  cools,  and  the  effect  of  drugs  on  the  solubility  of  uric  acid 
in  the  urine.  The  earliest  explanation  was  that  the  precipitation 
of  uric  acid  on  cooling  is  due  simply  to  a  decrease  in  solubility. 
Robin  and  VerdeiP  state  that  uric  acid  is  soluble  in  2,000  parts 
of  urine.  When  there  is  more  uric  acid  present  it  crystallizes  out. 
Prout  ^  and  Bartels,*  however,  knew  that  a  precipitation  of  uric 
acid  in  the  urine  did  not  mean  an  increased  excretion. 

The  most  widely  spread  view  is  that  the  uric  acid  in  the  urine 
exists  as  sodium  acid  urate.  On  account  of  the  fact  that  mineral 
acids  do  not  promptly  precipitate  all  the  uric  acid  from  solution 
in  urine,  Camerer  ^  thought  that  a  part  of  the  uric  acid  must  be 
combined  with  some  other  organic  compounds,  giving  a  body 
which  is  not  decomposed  by  acids. 

Riidel  ®  states  that  he  prepared  two  compounds  of  urea  and 
uric  acid  which  were  easily  soluble,  and  that  he  found  that  large 
amounts  of  urea  increase  the  solubility  of  uric  acid  in  urine. 

His  ^  repeated  the  experiments  of  Riidel,  but  was  not  able  to 
prepare  a  compound  of  urea  and  uric  acid.  He  showed  that 
the  slow  precipitation  of  the  uric  acid  from  urine  by  acids  is  due 
to  the  fact  that  when  the  uric  acid  is  set  free  from  the  urate  by 
acid,  a  supersaturated  solution  of  acid  is  formed  which  changes 
only  slowly  to  a  real  solution  and  gives  a  precipitation  of  practi- 
cally the  whole  of  the  uric  acid.     The  supersaturation  of  a  solu- 

*  A.  Nicolaier.  Ueber  die  therapeutische  Verwendimg  des  Urotropin  (Hexamethyl- 
entetramin).     Deutsche  Med.  Wochenschrift,  21,  541  (1895). 

2  C.  Robin  et  F.  Verdeil.  Traite  de  chimie  anatomique  et  physique.  Vol.  II,  399, 
1853,  Paris. 

3  Prout.     On  the  Nature  and  Treatment  of  Stomach  and  Renal  Diseases.     London,  1848. 

*  Bartels.  Untersuchungen  iiber  die  Ursachen  einer  gesteigerten  Harnsaure-Ausscheid- 
ung  in  Krankheiten.     Deutsche  Arch,  fur  klin.  Med.,  1,  13  (1865). 

=  W.  Camerer.  Zur  Lehre  von  der  Harnsaure  und  Gicht.  Deutsche  Med.  Wochenschrift, 
17,  356  (1891). 

^  G.  Riidel.  Zur  Kenntniss  der  Losungsbedingungen  der  Harnsaure  im  Harn.  Arch, 
fur  exp.  Path.  u.  Pharm.,  30,  469  (1892). 

'  W.  His.  Die  Harnsaureablagerungen  des  Korpers  und  die  Mittel  zu  ihrer  Losung. 
Therapie  des  Gegenwart,  Neue  Folge,  3,  434  (1901). 


72     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

tion  with  any  substance  does  not  continue  when  some  of  the  solid 
substance  is  present;  the  rapidity  of  precipitation  being  dependent 
on  the  intimacy  of  mixture  of  the  solution  and  solid  and  on  the 
extent  of  surface  offered  by  the  solid  to  the  liquid.  In  Heinze's 
method  of  determining  uric  acid  in  urine,  by  precipitation  with 
hydrochloric  acid,  large  crystals  of  uric  acid  are  formed  which 
fall  to  the  bottom  or  stick  to  the  sides  of  the  beaker  in  which  the 
determination  is  made.  Hence  sometimes  complete,  precipita- 
tion does  not  occur  for  weeks.  His  succeeded  in  precipitating 
all  the  uric  acid  from  urine  to  which  hydrochloric  acid  was  added 
by  adding  a  very  little  and  practically  negligible  amount  of  finely 
divided  uric  acid  and  rotating  the  solution  for  a  day  or  so.  The 
determination  of  the  uric  acid  in  this  way  gave  results  which 
agreed  closely  with  the  results  obtained  by  the  Salkowski  method. 
This  shows  that  the  uric  acid  in  the  urine  is  all  combined  as  an 
ordinary  salt  and  not  organically  combined,  and  that  conclusions 
arrived  at  by  physico-chemical  methods  in  pure  urate  solutions 
can  be  applied  to  the  urine. 

The  theories  of  Roberts,  Jones,  and  others  concerning  the  beha- 
vior of  the  quadriurates  in  the  urine  are  of  no  value,  since  the 
quadriurates  have  been  shown  not  to  exist.  This  subject  has 
already  been  discussed  at  length. 

When  urine  stands,  there  may  occur  a  precipitation  of  crystal- 
line uric  acid  which  does  not  redissolve  on  warming,  or  a  pre- 
cipitate of  amorphous  sodium  or  ammonium  urate  which 
redissolves  on  warming.  The  latter  gradually  changes  to  crystal- 
line uric  acid  on  standing.  A  small  amount  of  magnesium  urate 
has  been  found  in  the  sediment  by  Salkowski,^  and  a  small  amount 
of  calcium  urate  by  Delepine.^  The  old  view  expressed  by 
Scheube,^  that  the  precipitation  of  uric  acid  is  due  to  high  acidity 
and  high  concentration  of  uric  acid  was  the  prevailing  view  of  a 
generation  ago. 

This  precipitation  is  partly  due  to  the  fact  that  the  urates  are 
more  soluble  at  the  body  temperature  than  at  the  room  tempera- 
ture, but  in  greater  part  to  ch6mical  reaction. 

1  E.  Salkowski.  Ueber  die  Bildung  von  fliichtigen  Fettsauren  bei  der  ammoniakalischen 
Harngahrung.     Zeitschr.  fiir  physiol.  Chem.,  13,  272  (1889). 

^  S.  D^l^pine.  Ueber  Calciumurate.  Maly's  Jahresb.  iiber  die  Fortschritte  der 
Thierchemie,  18,  113  (1888). 

3  B.  Scheube.  Die  Harnsaureausscheidung  und  Sedimentbildung  bei  croupdser  Pneu- 
monie.     Arch,  der  Heilkunde,  17,  185  (1875). 


Chemistry  73 

Camerer  ^  showed  that  if  we  mix  a  saturated  sohition  of  acid 
sodium  urate  with  a  sokition  of  acid  sodium  phosphate  at  37°, 
a  mixture  which  reacts  acid  to  htmus  paper,  and  allow  it  to  cool, 
the  solution  becomes  alkaline,  and  crystals  of  uric  acid  appear. 
The  following  reaction  takes  place: 


NaC,H3N,03 

+ 

NaH.PO,      = 

=      C,H,N,03 

+ 

Na,HPO, 

sodium  acid  urate 

+ 

sodium  acid        - 
phosphate 

=           uric  acid 

+ 

alkaline  sodium 
phosphate 

Voit  and  Hofmann^  have  shown  that  when  urine  cools  and 
uric  acid  precipitates,  the  acidity  of  the  urine  decreases.  They 
showed  that  if  equivalent  amounts  of  sodium  acid  urate  and 
sodium  acid  phosphate  be  mixed,  the  acid  mixture  becomes 
alkaline,  and  uric  acid  precipitates.  On  this  account,  and  on 
account  of  the  fact  that  urine  always  contains  acid  sodium  phos- 
phate, Camerer  and  Voit  and  Hofmann  assumed  that  the  same 
reaction  takes  place  in  urine  that  takes  place  in  the  artificial 
solution. 

The  view  of  Voit  and  Hofmann  that  the  uric  acid  becomes 
less  acid  on  cooling  cannot  be  accepted,  for  until  very  recently 
the  acidity  of  urine  had  not  been  determined  with  any  approach 
to  accuracy.  The  titration  and  precipitation  methods  of  Maly,^ 
Freund,*  Freund  and  Topfer,^  Lieblein,**  Oliviero,^  Berlioz,  Lepinos 
and  Michel,^  de  Jager,**  Naegeli,^"  Arnstein,"  and  others  gave  results 
which  have  no  relation  to  the  true  acidity,  which  is  the  concen- 
tration of  the  hydrogen  ions.     The  acidity  of  the  urine  is  probably 

1  W.  Camerer.  Zur  Lehre  von  der  Harnsaure  und  Gicht.  Deutsche  Med.  Wochen- 
schrift,  17,  356  (1891). 

2  Voit  und  Hofmann.  Ueber  das  Zustandkommen  der  Harnsauresedimente.  Sitz- 
ungsber.  d.  Kngl.  bayerische  Akad.  de  Wissenschaft,  1,  279  (1867). 

3  R.  Maly.  Eine  Methode  zur  alkalinietrische  Bestimmung  der  Phosphorsaure  und  der 
alkalischen  Phosphate.     Zeitschr.  fiir  analytische  Chem.,   15,  417  (1876). 

*  E.  Freund.  Ueber  eine  Methode  zur  Bestimmung  von  einsachsauren  Phosphate 
neben  zweisach-sauren  Phosphate  im  Harne.  Centralbl.  fiir  die  Med.  Wissenschaften, 
30,  689  (1892). 

■'•  E.  Freund  und  G.  Topfer.  Ueber  die  Bestimmung  der  Alkalinitiit  und  Aciditat  des 
Urins.     Zeitschr.  fiir  physiol.  Chem.,  19,  84  (1894). 

s  Lieblein.  Ueber  die  Bestimmung  der  Aciditat  des  Hams.  Zeitschr.  fiir  physiol. 
Chem.,  20,  52  (1895). 

7  01i\dero.     Rep.  de  Pharmac.     (1897)  7  (Naegeli). 

8  Berlioz,  Lepinos,  and  Michel.     Chem.  Ztg.  Repertor,  1897  (Naegeli). 

9  L.  de  Jager.  Ueber  die  Reaktion  des  Harnes.  Zeitschr.  fiir  physiol.  Chem.,  24,  303 
(1898). 

-     .^°  (XNaegeli.     Zur  Aciditatsbestiinmung  des  Urins.      Zeitschr.  fiir  physiol.  Chem.,  30 

313  ('i"90(5T: 

11  R.  Arnstein.  Ueber  die  Aciditatsbestimmung  im  Harn.  Zeitschr.  fiir  physiol.  Chem., 
34,    1    (1901). 


74     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

due  in  great  part  to  NaH2P04.  This  is  a  very  weak  acid.  It 
dissociates  primarily  into  the  positive  ion  Na  and  the  negative 
ion  H2PO4.  The  negative  ion  HjPO^  dissociates  partly  into  the 
negative  ion  HPO4  and  the  positive  ion  H.  It  is  to  the  hydrogen 
ions  from  this  source  that  the  acidity  of  the  urine  is  probably 
due  in  large  part.  The  dissociation  of  HjPO^  into  H  and 
HPO4  is  only  very  slight,  not  at  all  comparable  even  to  the 
dissociation  of  hippuric  or  benzoic  acids,  for  Donath^  has  shown 
that  either  of  these  acids  can  change  Na2HP04  completely  to 
NaH2P04. 

If  we  attempt  to  determine  the  acidity  of  urine  hy  titration, 
and  add  a  little  sodium  hydrate,  the  hydroxyl  ions  from  the  sodium 
hydrate  immediatelj'"  combine  with  the  hydrogen  ions  from  the 
acid  phosphate  or  other  acid^  to  form  undissociated  water,  for  the 

small  size  of  K  in  the  equation =  K  =  .64  X  10~" 

tvHOH 

makes  it  impossible  for  more  than  an  insignificant  quantity  of 
hydrogen  ions  and  hydroxyl  ions  to  exist  together  in  solution. 
But  as  soon  as  these  hydrogen  ions  begin  to  disappear  more  are 
set  free  from  the  ion  H2PO4  in  order  that  the  equilibrium  expressed 

by   the   equation   j^ '■ — ^-  =  K,   where    Ch.    Chpo^,   and 

CH2PO4  are  the  concentrations  of  hydrogen,  HPO4  and  H2PO4 
ions,  respectively,  may  be  maintained.  This  dissociation  of 
H2PO4  continues  as  the  titration  proceeds  until  all  the  H2PO4 
has  broken  up  into  HPO4  and  H.  Titration  of  a  urine  with 
sodium  hydroxide  therefore  determines  the  concentration  of 
the  hydrogen  ions,  that  is,  the  acidity,  plus  the  concentration 
of  the  H2PO4  plus  the  concentration  of  the  other  acid  bodies. 
This  same  objection  applies  to  all  titration  and  precipitation  meth- 
ods. Bugarsky  and  Liebermann  ^  first  applied  a  principle  found 
in  Nernst's  textbook  on  physical  chemistry  to  the  analysis  of 
physiological  fluids.     This  method  was  modified  by  Rhorer  *  and 

1  Donath.      Sitzungsber.  d.  Wiener  Akad.,  1874. 

2  In  the  following  discussion  concerning  the  acidity  of  the  urine,  H2PO4  is  used  for 
brevity  to  represent  the  acids  of  the  urine  other  than  uric  acid.  It  is  probably  the 
principal  acid  present. 

3  L.  Bugarsky  und  L.  Liebermann.  Ueber  das  Bindungsvermogen  eiweissartiger  Korper 
fiir  das  Salzsaure  Natrium.     Pfliiger's  Archiv,  72,  51  (1898). 

*  L.  Rohrer.  Die  Bestimmung  der  Harnaciditat  auf  elektrometrischem  Wege.  Pfliiger's 
Archiv,  86,  586  (1901). 


Chemistry  75 

by  Hober  ^  and  applied  to  urine  and  blood  analysis.  The  prin- 
ciple of  the  method,  in  brief,  depends  upon  the  fact  that  if  we 
have  an  acid  solution,  of  urine,  for  example,  in  contact  with 
a  solution  of  dilute  hj-drochloric  acid,  there  will  be  a  difference 
of  potential  between  the  urine  and  the  acid.  The  difference  in 
potential  depends  upon  the  ratio  Ca:  Cb,  where  Ca  is  the  concen- 
tration of  the  hydrogen  ions  in  the  h\^drochloric  acid,  and  Cb  the 
concentration  of  the  hydrogen  ions  in  the  urine.  We  can  measure 
the  difference  in  potential,  determine  Ca  and  from  these  calculate 
Cb-  How  little  reliance  can  be  placed  on  conclusions  concerning 
the  acidity  of  the  urine  determined  by  titration  methods  may 
be  seen  from  the  fact  that  while  the  titration  methods  give  urine 

N 
an  average  acidity  of  about  ^,  the  electrochemical  methods  give 

the  concentration  of  hydrogen  ions  an  average  of  about  30  X  10~' 
(Rohrer  ^)  and  15  X  10""^  (Hober  and  Jankowsky^).  This  would 
indicate  that  the  titration  methods  give  a  result  from  10,000  to 
20,000  times  too  high. 

Zei^ner  ^  found  that  uric  acid  is  precipitated  by  monosodium 
phosphate  only  when  there  is  no  neutral  phosphate  in  excess  to 
hold  the  uric  acid  in  solution.  He  determined  the  amount,  re- 
action, urea,  uric  acid,  acid  phosphate,  neutral  phosphate,  and 
sediment  in  twenty-five  urines  and  came  to  the  conclusion  that 
the  precipitation  of  uric  acid  is  dependent  on  the  relation  between 
the  amount  of  uric  acid  and  the  amount  of  neutral  phosphate. 
If  the  ratio  of  the  amount  of  uric  acid  to  the  amount  of  neutral 
phosphate  present  is  greater  than  0.35  or  0.40  to  1,  there  is  a 
precipitate.  If  it  is  less,  there  is  no  precipitate.  The  acidity  of 
the  solution  does  not  seem  to  influence  the  formation  of  a  precipi- 
tate directly.  He  says  that  the  solubility  of  the  uric  acid  is 
dependent  on  the  size  of  the  uric  acid  production,  on  the  amount 
of  phosphate  excreted,  and  the  amount  of  acid  in  the  organism, 
since  this  latter  influences  the  relation  between  the  acid  and  the 
neutral  phosphates. 


1  R.  Hober.     Ueber  die  Hydroxylionen  des  Blutes.      Pfliiger's  Archiv,  81,  .522  (1900). 
-  L.  Rohrer.    Die  BestimmungderHamaciditat  auf  elektrometrischem  Wege.   Pfliiger's 

Archiv,  86,  586  (1901). 

2  Hober  xind  Jankowsky.     Die  Aciditat  des  Hams  vom  Standpunkt  der  lonealehre. 
Beitrage  zur  chemisehen  Physiologie  und  Pathologie,  III,  525  (1903). 

■*  Zerner.     Ueber  die  chemisehen  Bedingungen  fiir  die  Bildung  von  Harnsiiure    Sedi- 
menten.     Wien.  klin.  Wochenschrift,  6,  272  (1893). 


76     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Jahns  ^  showed  that  .467  grams  uric  acid  is  sohible  in  one  hter 
of  a  sokition  of  alkahne  sodium  phosphate  containing  1  gram  of 
this  salt.  Calculating  from  the  reaction  Na2HP04.12  H2O  + 
CsH.N^Og  =  NaH^PO^  +  NaCgHgNA  +  12  H^O,  we  should  expect 
one  gram  of  Na2HP04  to  react  with  .469  grams  of  uric  acid  so 
that  it  seems  probable  that  this  equation  represents  the  reaction 
that  takes  place.  The  fact  that  this  reaction  goes  in  the  opposite 
direction  in  the  urine  when  we  obtain  a  precipitate  of  crystal- 
line uric    acid    indicates   that  it   is  a  reversible   reaction.     The 

C  C 

equation  ^^  =  K,  in  which  Cj,  C2,  C3,  and  C4  represent  the  con- 
L3U4 

centrations  respectively  of  the  reacting  substances  Na2HP04, 
C5H4N4O3,  NaH2P04,  and  NaC5H3N403,  and  K,  a  constant,  deter- 
mines whether  the  reaction  written  above  takes  place  as  indi- 
cated, from  left  to  right,  or  in  the  reverse  direction,  from  right  to 

C  C 
left.     This  equation    J' J'  =  K  is   merely  an  expression   of   the 
L/3U4 

mass  action  law  of  Guldberg  and  Waage.  K  is  a  constant,  which 
can  be  calculated  from  the  dissociation  constants  of  the.  four 
electrolytes  present.  These  dissociation  constants  are  dependent 
merely  on  the  compound  itself,  the  temperature  of  the  solution, 
and  can  be  determined  by  experiment.  In  the  last  instance, 
therefore,  since  the  dissociation  constants  determine  the  amount 
of  dissociation  of  the  electrolytes,  the  direction  in  which  the 
reaction  takes  place  depends  on  the  relative  concentration  of 
the  reacting  substances  and  upon  their  relative  dissociation.  The 
dissociation  of  any  one  of  them  depends  on  the  temperature,  upon 
the  concentration  of  each  of  the  others,  and  also  on  the  concen- 
tration from  some  other  source  of  the  ions  into  which  it  disso- 
ciates. Sodium  chloride,  for  instance,  which  serves  as  a  source 
of  sodium  ions,  can  influence  the  dissociation  of  sodium  acid 
urate,  which  also  dissociates  in  solution  and  gives  sodium  ions. 
K  may  have  such  a  value  that  the  reaction  takes  place  in  both 
directions  until  finally  an  equilibrium  is  reached  in  which  some 
of  all  the  reacting  substances  are  present. 

Smale  ^  found  that  uric  acid  is  soluble  in  a  solution  of  the  urinary 
salts  of  average  composition  to  the  extent  of  .63  grams  in  the 

1  Jahns.  Ueber  die  Loslichkeit  der  Harnsaure  in  Salzlosung.  Arch.  f.  Pharmacie, 
221,  511  (1882). 

'■^  F.  Smale.  Beitrage  zur  Kenntniss  der  Losungsbedingungen  der  Harnsaure  im  Harn. 
Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  25,  239  (1895). 


Chemistry  77 

daily  amount  of  urine.  Since  the  quantitative  composition  of 
the  urine  in  salts  is  very  variable,  variable  enough  to  make  a  con- 
siderable difference  is  its  dissolving  power  for  uric  acid,  Smale's 
work  can  be  of  little  value. 

Strauss  ^  found  that  administration  of  calcium  carbonate  in- 
creased the  solvent  power  of  urine  for  uric  acid.  He  found  like- 
wise that  calcium  carbonate  decreased  the  amount  of  sodium  acid 
phosphate  in  the  urine  without  influencing  the  amount  of  sodium 

alkaline  phosphate.      To  this  increase  in  the  ratio ,-,  !-t  t^^^^  he 

J\aH2P04 

attributed  the  increased  solubility  of  the  uric  acid.  Posner  - 
and  Lehmann  ^  had  previously  found  that  administration  of  cal- 
cium carbonate  gave  the  urine  a  greater  solvent  power  for  uric  acid. 
The  work  of  Posner,  Lehmann,  and  Strauss  is  open  to  criticism  and 
their  conclusions  thrown  into  great  doubt  on  account  of  the  fact 
that  the  methods  used  in  their  work  were  of  doubtful  accuracy. 

Mordhorst  *  found  that  the  sodium  acid  urate  decomposes  in 
distilled  water,  giving  uric  acid.  This  decomposition  is  slower 
in  a  solution  of  sodium  chloride  and  ceases  in  a  solution  containing 
alkaline  disodium  phosphate.  Acid  hastens  the  decomposition. 
In  a  neutral  solution  containing  both  alkaline,  disodium  phos- 
phate and  acid  sodium  dihydrogen  phosphate,  the  decomposition 
is  slow,  for  the  sodium  set  free  from  the  urate  changes  some  of 
the  acid  sodium  phosphate  to  alkaline  sodium  phosphate.  Mord- 
horst says  that  the  decomposition  of  the  urate  and  precipitation 
of  uric  acid  is  hastened  by  high  acidity,  high  value  of  the  ratio 

>  low  concentration  of  salts,  especially  sodium  chloride, 

urea  '      r  j 

and  by  low  concentration  of  coloring  matter;  he  does  not  think 
that  a  urate  sediment  can  come  down  in  an  alkaline  urine. 

As  we  have  seen,  His  and  Paul  found  the  dissociation  constant 
for  uric  acid  very  small,  so  small,  in  fact,  that  the  concentration 
of  the  hydrogen  ions  in  a  saturated  solution  of  uric  acid  is  com- 

1  J.  Strauss.  Ueber  die  Einwirkung  des  kohlensauren  Kalkes  auf  den  menschlichen 
Stoffwechsel,  ein  Beitrag  zur  Therapie  der  harnsauren  Nierenkonkretionen  nebst  Bemerk- 
ungen  iiber  AUoxurkorperausscheidung.     Zeitschr.  fiir  klin.  Med.,  31,  493  (1896). 

2  Posner.  Zur  Therapie  der  Harnsaureiiberschusses.  Zeitschr.  fiir  klin.  Med.,  XVII 
(1890)  (cited  by  Strauss). 

3  L.  Ijchmann.  Zur  Wirkung  des  Kohlensauren  Kalkes  und  der  kohlensauren  Mag- 
nesia.    Berl.  klin.  Wochenschrift,  19,  320  (1882). 

4  C.  Mordhorst.  Die  Entstehung  und  Auflosung  der  Harnsaureverbindungen  ausser- 
halb  und  innerhalb  des  menschlichen  Korpers.     Zeitschr.  fur  klin.  Med.,  32,  65  (1897). 


78      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

parable  with  the  concentration  of  the  hydrogen  ions  in  pure 
water.  This  explains  the  decomposition  of  sodium  acid  urate 
by  water,  noticed  by  Mordhorst.  In  an  aqvieous  solution  of  a  salt 
of  a  very  weak  acid,  some  of  the  acid  itself  is  formed.  In  the 
case  of  sodium  urate  the  hydrogen  ions  from  the  water  react  with 
the  negative  uric  acid  ions  from  sodium  acid  urate  until  the  equi- 

librium  expressed  by  the  equation    ^   =  K  is  reached.    Chu? 

Ohu 

which  we  have  used  to  indicate  undissociated  uric  acid,  is  a 
small  constant,  and  the  equilibrium  may  require  formation  of 
more  HU  than  can  remain  in  solution.  In  this  case  the  uric 
acid  will  precipitate.  Acids,  of  course,  hasten  the  precipitation 
and  alkalies  stop  it. 

At  this  point  it  might  be  well  to  speak  of  the  work  of  Pfeiffer. 
In  1886  ^  he  found  that  if  a  urine  be  poured  through  a  filter  covered 
with  a  layer  of  uric  acid,  more  or  less  of  the  uric  acid  of  the  urine 
is  given  up  to  the  filter.  He  stated  that  the  uric  acid  exists  in 
the  urine  in  two  forms :  "  free  uric  acid  "  —  by  which,  however,  he 
did  not  mean  chemically  free  —  and  "  combined  "  uric  acid  The 
"  free  "  uric  acid  is  that  given  up  to  the  uric  acid  filter.  A  few 
years  later  ^  he  came  to  the  conclusion  that  the  "  free  uric  acid  " 
is  that  which  comes  down  crystalline  in  urine,  and  the  "  com- 
bined "  uric  acid  that  which  appears  as  amorphous  sediment. 
He  believed  that  in  the  periods  free  from  attacks  gouty  people 
have  the  uric  acid  to  a  very  large  extent  in  the  "  free  "  form,  and 
that  if  the  urine  of  a  person  be  filtered  through  a  uric  acid  filter 
and  then  on  treatment  with  hydrochloric  acid  the  filtrate  does 
not  give  a  precipitate  of  uric  acid  a  certain  diagnosis  of  gout  can 
be  made.  He  says  that  in  the  attacks  of  gout,  the  uric  acid  pre- 
viousty  almost  entirely  "  free  "  becomes  almost  entirely  "  com- 
bined." This  last  statement  that  in  gout  the  uric  acid  is  almost 
entirely  free  has  been  contradicted  by  Feliziani,^  and  further, 
this  author  and  also  Schetelig  *   have  found   plenty  of  "  free  " 

1  E.  Pfeiffer.  Zur  Aetiologie  und  Therapie  der  harnsauren  Steine.  Verhandl.  des  5t 
Kongr.  ftir  innere  Medizin,  Wiesbaden,  1886,  444. 

2  Ibid.  Die  Natur  und  Behandlung  der  Gicht.  Verhandl.  des  8t  Kongr.  fiir  innere 
Medizin,  Wiesbaden,  1889,  166. 

3  E.  Feliziani.  Sul  valore  della  preeipitabilita  dell'  acido  urico,  deterniinato  col  metodo 
di  Pfeiffer  nella  diagnosi  della  Gotta.  Rivista  gener.  ital.  di  chim.  med.,  Pisa,  1890,  2,  360. 
Also  Revue  des  Sciences  Med.,  1890,  460. 

*  A.  ScheteUg.  Discussion  of  E.  Pfeiffer's  article.  Die  Natur  und  Behandlung  der  Gicht. 
Verhandl.  des  8t  Kongr.  fur  innere  Medizin    1889,  212. 


Chemistry  79 

uric  acid  in  urine  of  healthy  persons   and  others  who  have  not 
gout. 

Posner  and  Goldenberg/  and  Roberts  -  found  that  the  amount 
of  uric  acid  given  up  to  the  filter  is  dependent  on  a  number  of 
circumstances,  such  as  rapidity  of  filtration,  acidity,  and  so  forth. 
Rosenfeld  ^  found  that  some  of  the  uric  acid  is  given  up  even  to 
the  filter  paper. 

Ritter^  prepared  a  solution  of  phosphoric  acid  containing  a 
known  amount  of  P2O5  and  a  solution  of  disodium  phosphate 
containing  the  same  amount  of  P2O5.  By  mixing  these  two 
solutions  in  different  proportions,  he  could  obtain  solutions  con- 
taining any  proportions  of  alkaline  sodium  phosphate  and  acid 
sodium  phosphate.  He  also  prepared  solutions  containing  known 
quantities  of  sodium  acid  urate  and  urea.  By  mixing  the  four  solu- 
tions he  could  simulate  the  conditions  occurring  in  different  urines. 

In  the  presence  of  disodium  hydrogen  phosphate,  NaaHPO^, 
the  uric  acid  set  free  from  the  acid  urate  by  sodium  acid  phosphate, 
NaH2P04,  is  kept  in  solution.  Since,  however,  the  alkaline 
sodium  phosphate,  NajHPO^,  dissolves  only  that  uric  acid  set  free 
from  the  urate  and  does  not  help  dissolve  the  sodium  acid  urate 
itself,  Zerner  was  wrong  in  believing  that  the  solubility  of  uric 
acid  in  the  urine  is  dependent  wholly  on  the  ratio  of  the  uric  acid 
to  the  NaaHPO^. 

Up  to  a  certain  concentration  of  NajHPO^,  Ritter  showed  that 
uric  acid  crystals  can  precipitate.  Over  that  concentration, 
crystalline  uric  acid  cannot  precipitate.  The  concentration  of 
the  uric  acid  seems  to  influence  only  the  rate  of  precipitation. 

Another  action  of  the  NajHPO^  is  to  increase  the  concentration 
of  the  Na  ions,  and  thus  to  decrease  the  solubility  of  the  sodium 
acid  urate.  This  explains  the  formation  of  urate  sediment  in 
alkaline  urine.  Na2HP04,  as  well  as  sodium  bicarbonate,  acetate, 
nitrate,  sulphate,  and  so  forth,  gives  a  white  precipitate  of  "  kugel  " 
urates.  This  shows  that  there  is  no  formation  of  a  double  salt 
of  phosphate  and  urate  of  sodium. 

1  Posner  und  Goldenberg.  Zur  Auflosung  harnsaurer  Konkretionen.  Zeitschr.  fur  klin. 
Med.,  13,  580  (1887). 

2  W.  Roberts.  Ueber  Pfeiffer's  Probe  fiir  latente  Gicht.  Maly's  Jahresb.  iiber  die 
Fortschritte  der  Thierchemie,  21,  403  (1891). 

3  Rosenfeld  und  Orgler.  Zur  Behandlung  der  harnsauren  Diathese.  Centralbl.  fur  in- 
nere  Medizin,  17,  42  (1896). 

4  A.  Ritter.  Ueber  die  Bedingungen  fur  die  Entstehung  harnsauren  Sedimente,  ein 
Beitrag  zur  Theorie  der  Gicht.     Zeitschr.  fiir  Biologie,  35,  155  (1897). 


80      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

In  the  case  of  formation  of  crystalline  uric  acid  sediment  there 
is  either  an  entire  absence  of,  or  only  very  little,  disodiiim  phos- 
phate. The  acidity  may  be  either  high  or  low.  The  acid  strength 
determines  only  the  rapidity  of  precipitation. 

Many  urines  give  a  precipitation  of  uric  acid  only  after  a  very 
long  time.  This  precipitation  may  be  due  to  a  gradual  change 
of  Na2HP04  to  NaHaPO^  by  bacteria  or  some  other  process. 

Ritter  likewise  explained  the  results  obtained  by  Pfeiffer  with 
the  uric  acid  filter.  If  we  take  two  equal  portions  of  the  same 
urine,  to  one  add  .3-.5  grams  of  uric  acid,  allow  them  to  stand 
a  few  hours  and  then  filter  through  a  uric  acid  filter,  the  filtrate 
of  the  portion  to  which  uric  acid  has  been  added  contains  less 
uric  acid  than  the  other.  Part  of  the  uric  acid  added  is  dissolved 
by  alkaline  sodium,  phosphate,  forming  sodium  acid  urate,  and  the 
alkaline  phosphate  changes  to  acid  sodium  phosphate.  Then 
the  undissolved  uric  acid  causes  a  large  part  of  the  uric  acid  in 
solution  to  crystallize  out.  The  explanation  of  the  large  amount 
of  "  free  "  uric  acid  found  by  Pfeiffer  in  the  urine  of  those  inclined 
to  gout  is  that  such  urine  probably  contains  only  a  small  amount 
of  alkaline  phosphates.  The  filtrate  from  a  urine  passed  through 
a  uric  acid  filter  may  contain  the  same,  or  more,  or  less,  uric  acid 
than  before  it  is  filtered.  The  result  is  dependent  on  the  velocity 
of  filtration,  the  acidity  of  the  urine,  the  concentration  of  uric 
acid,  the  temperature,  the  height  of  uric  acid  layer,  and  so  forth. 

At  the  congress  for  internal  medicine  at  Wiesbaden  in  1902, 
Klemperer  ^  read  a  paper  in  which  he  stated  that  the  uric  acid 
in  the  urine  exists  chiefly  in  the  form  of  a  salt  and  as  free  uric 
acid  in  the  colloidal  form,  and  that  there  was  usually  rather  more 
of  the  free  acid  than  the  salt.  He  determined  the  total  uric  acid 
in  a  quantity  of  urine  by  the  Ludwig-Salkowski  method,  and 
then  after  shaking  the  same  quantity  of  urine  with  crystalline 
uric  acid  for  a  couple  of  days,  he  filtered  and  determined  the  uric 
acid  in  the  filtrate.  He  assumed  that  shaking  with  crystalline 
uric  acid  would  precipitate  colloidal  uric  acid  and  only  colloidal 
uric  acid.  The  uric  acid  in  the  filtrate  then  would  be  that  present 
as  urate  and  the  difference  between  this  value  and  the  total  would 
be  the  uric  acid  in  the  colloidal  form.  He  further  attempted  to 
show  that  urochrome  is  the  agent  which  keeps  uric  acid  colloidal 

1  G.  Klemperer.  Untersuchungen  iiber  die  Losungsverhaltnisse  der  Harnsaure  im 
Urin.     Verhandl.  des  20t  Kongr.  fiir  innere  Medizin,  Wiesbaden,  1902,  219. 


Chemistry  81 

in  the  urine.  McCrudden  ^  showed  that  Klemperer's  work  was 
open  to  criticism  from  a  number  of  points,  that  he  had  merely 
done  in  a  slightly  different  way  what  Pfeiffer  ^  had  done  with 
his  uric  acid  filter,  and  that  his  results  were  of  no  value,  since  the 
explanation  that  Ritter  ^  gave  of  Pfeiffer's  results  applies  equally 
well  to  Klemperer's. 

Singer/  too,  has  recently  spent  some  time  in  studying  the  effect 
of  foods  and  drugs  on  the  relative  quantities  of  free  and  combined 
uric  acid  in  the  urine. 

It  seems  probable  from  the  work  of  Klemperer  ^  and  also  from 
that  of  Roberts^  and  Herter^  that  urochrome  may  be  one  of  the 
agents  which  retard  the  precipitation  of  uric  acid  when  the  urine 
cools. 

An  explanation  of  the  behavior  of  uric  acid  in  the  urine  is 
offered  if  we  turn  to  physical  chemistry  for  assistance.^     The 

affinity  constant  K  in  the  equation  — =  K  is  .00000151  ac- 

Chu 
cording  to  His    and  Paul.^     (Ch  stands  for    the    concentration 
of   the   hydrogen   ions,  Cu   for  the   concentration   of  the  nega- 
tive  uric   acid   ions,   and   Chu  for  the  undissociated  uric  acid.) 
Chu    is    a     constant,     equal,     at     18°,     to      .0001363.^      Then 

^^  ^  ^^'  =  .00000151,    or    the    solubilitv  product    Ch  X  Cu  = 
.0001363 

.00000151  X  .0001363  =  206  X  10 -^^  (-j)_  j^  the  1,500  cc.  of 
urine   daily  excreted,   there   is    on  the  average    .75   gram   uric 

1  F.  McCrudden.  A  Criticism  of  Klemperer's  Work  on  the  Condition  of  Uric  Acid  in 
the  Urine.     Boston  Medical  and  Surgical.  Journal,  August,    1903. 

2  E.  Pfeiffer.  Zur  Aetiologie  und  Therapie  der  harnsauren  Steine.  Verhandl.  des  ot 
Kongr.   fiir  innere   Medizin,  Wiesbaden,    1886,   444. 

Ihid.  Die  Natur  und  Behandlung  der  Gicht.  Verhandl.  des  8t  Kongr.  fiir  innere 
Medizin,  Wiesbaden,  1889,  166. 

3  A.  Ritter.  Ueber  die  Bedingungen  fiir  die  Entstehung  harnsaurer  Sedimente,  ein 
Beitrag  zur  Theorie  der  Gicht.     Zeitschr.  fiir  Biol.,  35,  155  (1897). 

*  H.  Singer.  Beitrage  zur  Losungsfahigkeit  des  Harns  fiir  die  Harnsaure.  Dt.-;ch. 
Aerzte  Zeitung,  1903,  505. 

5  G.  Klemperer.  Untersuchungen  tiber  die  Losungsverhaltnisse  der  Harnsaure  im 
Urine.     Verhandl.  des  20t   Kongr.  fiir  innere  Medizin,  Wiesbaden,  1902,  219. 

8  W.  Roberts.  Chemistry  and  Therapeutics  of  Uric  Acid  Gravel  and  Gout.  (Croonian 
Lectures.)     Lancet,  1902. 

^  C.  A.  Herter.  Some  Practical  Points  Regarding  the  Excessive  Excretion  of  Uric 
Acid.     New  York  Medical  Journal.  58,  8  (1893). 

8  See  also  F.  McCrudden.  The  Application  of  Physical  Chemistry  to  the  Study  of  Uric 
Acid  in  the  Urine.  Read  at  the  Meeting  of  the  Am.  Ass.  for  the  Advancement  of  Science, 
St.  Louis,  December  28,  1903,  and  Journal  of  the  Am.  Chem.  Soc,  March,  1904. 

^W.  His  und  T.  Paul.  Physikalisch-eheraische  Untersuchungen  iiber  das  Verhalten 
der  Harnsaure  und  ihrer  Salze  in  Liisungen.  I.  Abhandlung.  Zeitschr.  fiir  physiol.  Chem., 
31,    1    (1900). 


82      The  Chemistry,  Physiology,  omd  Pathology  of  Uric  Acid 

acid  excreted  in  the  form  of  sodium  acid  m'ate.  This  is  .5 
gram  per  hter,  or,  dividing  by  the  molecular  weight,  about 
.003  gram  molecules  per  liter.  A  salt  in  such  dilute  solution 
is  almost  completely  dissociated,  so  that  in  an  aqueous  solu- 
tion of  sodium  acid  urate,  of  the  concentration  found  in  the 
urine,  Cu.  in  equation  1,  becomes  .003.     Then  Ch  X  .003  =  206  X 

206  Y  10~^^ 
10-^2  or  Ch=  ^^^^^^^^ —  =7.Xl0-«-     If  2  grams  per  day  uric 

•UUo 

acid  were  excreted,  a  rather  high  limit,  Ch  would  be  about 
2  X  10""^.  If  only  .1  gram  uric  acid  were  excreted  per  day 
with  the  ordinary  amount  of  urine,  or  if  in  a  diseased  con- 
dition the  amount  of  urine  should  increase  to  4  liters,  and 
only  .4  gram  uric  acid  were  excreted,  Ch  would  increase  to 
34  X  10""^.  In  other  words,  in  an  aqueous  solution  of  sodium 
urate  of  the  concentration  of  average  urine,  we  can  have  hydrogen 
ions  present  in  a  concentration  of  only  about  7.  X  10~^  without 
a  precipitation  of  uric  acid.  With  the  ordinary  variations  in 
the  amount  of  urate  present  in  urine,  the  figure  would  vary  from 
about  4  X  10~^  to  15  X  10~^  In  extreme  pathological  cases 
it  might  vary  from  2  X  10~^  to  35  X  10~^  If  the  concentration 
of  the  hydrogen  ions  increases  beyond  the  limit  set  by  the  equa- 
tion Ch  X  Cu  =  206  X  10"^^,  then  undissociated  uric  acid  will 
form,  and  precipitation  of  uric  acid  will  occur. 

The  average  acidity  of  urine,  expressed  by  the  concentration 
of  the  hydrogen  ions,  is  300  X  10~^  according  to  Rhorer,^  and 
150  X  10~^  according  to  Hober  and  Jankowsky.^  Rhorer  found 
the  value  to  vary  in  different  urines  from  40  X  10~Ho  610  X  10~^ 
Hober  and  Jankowsky  obtained  results  varying  from  100  X  10"* 
to  1,000  X  10~*.  In  a  very  few  pathological  cases  the  value 
was  slightly  outside  these  limits.  We  can  see,  then,  why  uric 
acid  should  precipitate  from  cold  urine.  The  concentration  of 
the  hydrogen  ions  is  too  great  to  permit  the  presence  of  the  large 
quantity  of  negative  uric  acid  ions  present,  so  precipitation  of 
uric  acid  occurs.  The  fact  that  uric  acid  does  not  always  precipi- 
tate immediately  from  the  cold  urine  is  due,  as  His  ^  has  shown, 

1  L.  Rhorer.  Die  Bestimmiing  der  Harnaciditat  avif  elektrometrischen  Wege.  Pfliiger's 
Archiv,  86,  586  (1901). 

2  Hober  und  Jankowsky.  Die  Aciditat  des  Hams  vom  Standpunkt  der  lonenlehre. 
Beitrage  zur  chemischen  Physiologie  und  Pathologie,  III,  525  (1903). 

3  W.  His.  Die  Harnsaureablagerung  des  Korpers  und  die  JTittel  zu  ihrer  Losung 
Therapie  des  Gegenwart,  Neue  Folge,  3,  434  (1901). 


Chemistry  83 

to  the  fact  that  the  insokible  uric  acid  goes  into  the  colloidal 
condition  and  does  not  precipitate  for  some  time.  Even  when 
hydrochloric  acid  is  added  to  the  solution,  some  of  this  insoluble 
uric  acid  is  not  precipitated  for  weeks.  As  Pfeiffer/  His,^  and 
Klemperer  ^  have  shown,  this  colloidal  uric  acid  can  be  precipi- 
tated by  thoroughly  shaking  the  solution  with  uric  acid. 

Klemperer  showed  that  when  urine  is  thoroughly  shaken  with 
solid  uric  acid,  a  variable  part,  but  not  the  whole,  of  the  uric  acid 
present  is  precipitated  from  solution.  An  explanation  of  this 
fact  is  easily  given.  The  acidity  of  the  urine  as  determined  by 
titration  (that  is,  "  potential  acidity  "),  is  about  ten  thousand 
times  as  great  as  the  real  acidity.  We  have  seen  that  as  soon  as 
the  "  actual  "  hydrogen  ions  present  are  used  up  by  titration 
with  alkali,  more  of  the  "  potential  "  hydrogen  ions  are  set  free  to 

preserve  the  equilibrium  indicated  by  the  equation -^^ ^=K; 

Cha 
where  Cha  is  used  to  indicate  the  acid  or  acid  bodies  to  which 
urine  owes  its  acidity,  —  probably  chiefly  NaHjPO^.  The  same 
thing  occurs  when  the  "  actual  "  H  ions  are  carried  out  of  solu- 
tion by  precipitation  as  uric  acid.  If  merely  enough  uric  acid 
disappears  from  solution  to  use  up  the  actual  hydrogen  ions 
present,  the  actual  acidity  of  the  solution  remains  practically 
unaffected,  for  immediately  more  H  ions  are  set  free  from  the 
undissociated  HA  until  equilibrium  is  reached.     In  the  equation 

— -=  K,  we  know  that  K  is  small,  that  is,  ChoPo.  is 

large  in  comparison  with  Ch  and  Chpo4-  Then  for  small  changes 
in  CH2PO4  due  to  setting  free  of  H  and  HPO4  to  establish  equi- 
librium after  disappearance  of  H  on  account  of  precipitation  of 
uric  acid,  we  can  consider  CH2PO4  constant  practically.  We  know 
that  on  account  of  the  presence  of  Na2HP04,  largely  dissociated 
to  Na2  and  HPO4,  CHPO4  is  large  in  comparison  with  Ch,so  that 
for  small  changes  in  CHPO4,  due  to  the  further  dissociation  of 
H2PO4  to  establish  equilibrium  after  disappearance  of  the  "actual" 
H  ions,  CHPO4  ^^y  b®  considered  practically  constant.      If  we 

1  E.  Pfeiffer.  Zur  Aetiologie  und  Therapie  der  harnsauren  Steine.  Verhandl.  des  5t 
Kongr.  fiir  innere  Medizin,  Wiesbaden,   1886,  444. 

-  W.  His.  Die  Hamsaureablagerung  des  Korpers  tind  die  Mittei  zu  ihrer  Losung. 
Therapie  des  Gegenwart,  Neue  Folge,  3,  434  (1901). 

3  G.  Klemperer.  Untersuchungen  iiber  die  Losungsverhaltnisse  der  Harnsiiure  im 
Urine.     Verhandl.  des  20t  Kongr.  fiir  innere  Medizin,  Wiesbaden,  1902,  219. 


84     The  Chemistry  J  Physiology,  and  Pathology  of  Uric  Acid 

p/  w     p/ 

consider    — — -*  =  K  the  initial  equation,  then  after  pre- 

C  H2PO4 

cipitation  of  a  very  little  uric  acid  Ave  have  the  new  equation 

— ^:^^ ^^^*  =  K,    where     C"hpo4  =  C'hpo^,    approximately, 

^  H2PO4 

and  C"h2P04  =  C'h2P04,  approximately.  Therefore  Ch  is  approxi- 
mately constant.  In  other  words;  after  a  small  amount  of  uric 
acid  has  precipitated,  the  concentration  of  the  H  ions  is  almost 
the  same  as  before,  so  that  the  solubility  constant  for  uric  acid 
is  still  exceeded,  and  more  uric  acid  precipitates.  But,  as  uric 
acid  precipitates  in  larger  amounts,  the  loss  of  H  ions  from  the 
H2PO4  will  decrease  the  value  for  CH2PO4,  and  the  HPO4  ions 
formed  at  the  same  time  will  increase  the  value  for  CHPO4  ^^ 
the  equation.  Then  Ch  must  decrease  in  order  to  maintain 
equilibrium.  Obviously  a  time  will  come  when  this  decrease  in 
H  ions  and  the  decrease  in  negative  U  ions  brought  about  through 
loss  of  uric  acid  by  precipitation  will  be  so  great  that  Ch  X  Cu  will 
be  less  than  206  X  1 0~^^.  Then  no  more  uric  acid  will  precipitate. 
Let  us  take  the  value  for  normal  urine  Ch  =  150  X  10~^,  and 
the  amount  of  uric  acid  excreted  as  .75  grams  in  1,500  cc.  urine. 
Then  Cu  =  -003.  Let  us  suppose  that  by  spontaneous  precipi- 
tation of  uric  acid,  or  by  addition  of  alkali,  Ch  has  decreased  to 
15  X  10-^  or  to  T^,  its  initial  value,  then  Ch  X  Cu  =  206  X  lO-^^ 

90fi  V  1 0-12 
becomes  15  X  10-«  X  Cu  =  206  X  10-^==  and  Cu  =  ,  - 

15  X  10~^ 

15  X  10~*  =  .0015.  In  this  case  equilibrium  is  reached  when  the 
acidity  of  the  urine  has  been  decreased  to  yV  of  its  initial  value 
and  i  the  uric  acid  has  precipitated. 

Ritter,^  it  will  be  remembered,  found  that  the  equilibrium  is 
reached  more  quickly,  that  is,  less  uric  acid  is  precipitated  when 
large  quantities  of  NaaHPO^  are  present  than  when  small  quan- 
tities of  Na2HP04  are  present.  This  is  easy  to  understand. 
The  addition  of  Na2lIP04  means  the  addition  of  HPO4  ions. 
The  formation  of  H2PO4  by  the  union  of  even  a  large  part  of  the 
H  ions  present  with  HPO4  would  scarcely  affect  the  total  value 
for  Ch2P04>  since  CH2PO4  is  so  large  in  comparison  with  Ch-  From 
the  equation  Ch  X  CHPO4  =  K  X  CH2PO4  (a  constant  in  this 
case),  we  can  see  that  the  addition  of  HPO4  will  decrease  Ch  in 

1  A.  Ritter.  Ueber  die  Bedingungen  fiir  die  Entstehung  harnsaurer  Sedimente,  ein 
Beitrag  zur  Theorie  der  Gicht.     Zeitschr.  ftir  Biologie,  35,  155  (1897). 


Chemistry  85 

the  same  ratio  as  CHPO4  increases.  Further,  we  know  that 
NaoHPO^  is  alkahne.  That  is,  a  solution  of  NajHPO^  contains 
OH  ions.  (This  is  due  to  the  fact  that  the  reaction  Na2++  + 
HPO4 —  +  H+  +  OH-  =  Na2+  +  +  H.PO  -  +  OH"  takes  place  to 
some  extent.)  On  addition  of  a  solution  of  Na2HP04  to  one 
of  NaH2P04,  the  reaction  of  H  +  +  OH"  =  HOH  takes  place, 
thus  still  further  decreasing  the  concentration  of  the  H  ions. 
Therefore  the  value  of  Ch  in  the  equation  Ch  X  Cu  =  206  X  IQ-^^ 
will  be  reached  sooner  when  Na2HP04  is  added  to  the  solution, 
and  will  necessitate  the  precipitation  of  a  smaller  quantity  of 
uric  acid  before  equilibrium  is  reached. 

The  effect  of  a  small  addition  of  alkali  to  a  cold  urine  would 
be  the  same  as  the  effect  of  a  slight  precipitation  of  the  uric  acid. 
The  hydroxyl  ions  from  the  alkali  would  combine  with  the  "  act- 
ual "  H  ions,  in  order  that  the  value  Ch  X  Cqh  =  .64  X  10"" 
should  not  be  exceeded.  But  then,  just  as  the  precipitation  of 
a  little  uric  acid  by  carrying  away  the  actual  hydrogen  affects 

the  values  in  the  equation  — *  =  K   very  little,   so  the 

CH2PO4 

value  of  Ch  would  not  be  affected  by  the  addition  of  a  little  alkali. 
Therefore,  since  Ch  X  Cu  =  a  constant,  and  the  addition  of  a  little 
alkali  does  not  change  Ch,  Cu  is  not  changed,  so  that  the  addition 
of  a  little  alkali  does  not  change  the  solubility  of  uric  acid  in 
cold  urine.  It  has,  in  fact,  been  shown  by  experiment,  as  we 
shall  see  later,  that  partial  neutralization  of  the  acidity  of  a  cold 
urine  by  alkali  does  not  give  it  the  power  of  dissolving  uric  acid 
crystals.  When,  however,  enough  alkali  is  added  to  very  de- 
cidedly decrease  CH2PO4,  and  correspondingly  increase  ChpOi? 
Ch  is  decreased  to  maintain  equilibrium,  and  when  Ch  is  decreased 
enough  to  approach  the  concentration  allowed  by  the  equation 
Ch  X  Cu  =  206  X  10"^^,  then  the  solubility  of  uric  acid  begins 
to  be  increased. 

With  increase  in  temperature,  K  generally  increases.  Chu? 
the  value  for  the  solubility  of  the  undissociated  uric  acid,  also 
increases.  Therefore,  Ch  X  Cu  =  K  X  Chu  is  very  largely  in- 
creased, and  since  Cu  is  a  constant  for  any  given  urine,  the  value 

Ch= ^ is  greatly  increased.     In  other  words,  the    con- 

Cu 
centration  of  the  H  ions,  which  can  exist  in  solution  with  a 
definite  amount  of  negative  urate  ions,  is  increased  with  the 


86     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

temperature.  With  increase  in  temperature,  there  is  also  an 
increase  in  the  dissociation  of  the  other  weak  bases  and  acids  in 
the  urine.  But  the  OH  ions  from  the  bases  neutrahze  the  H 
ions  from  the  acids,  according  to  the  equation  H  X  OH  =  HOH. 
If  the  increase  in  the  supply  of  the  OH  ions  is  equal  to  the 
increase  in  the  supply  of  the  H  ions  on  warming,  the  actual  con- 
centration of  H  ions  will  remain  the  same  with  increase  in  tem- 
perature.    In  the  equation  Ch  X  Cu  =  K  X  Chu  or  Cu= ^ — ^ 

we  have,  in  such  a  case,  K  increasing,  Chu  increasing,  and  Ch  con- 
stant. Therefore,  Cu  must  increase.  That  is,  the  amount  of 
negative  uric  acid  ions  or  sodium  urate  that  can  remain  in  solu- 
tion is  greater.  Or,  to  put  it  more  generally,  if  the  increase  in 
concentration  of  OH  ions  is  rapid  enough  to  prevent  the  actual 
concentration  of  the  H  ions  in  any  urine  from  increasing  as 

rapidly  as  the  value  for  Ch  in  the  equation  Ch  =  —      ^  ,  then 

Cu 

the  solubility  of  the  uric  acid  will  increase  with  increase  in  tem- 
perature. If  the  concentration  of  the  OH  ions  increases  faster 
than  the  concentration  of  the  H  ions,  the  actual  value  for  the 
concentration  of  the  H  ions  will  decrease  with  increase  in  tempera- 
ture. In  this  case,  which,  as  we  shall  see,  is  probably  the  condi- 
tion in  normal  urine,  the  solubility  of  the  uric  acid  will  increase 
with  rise  in  temperature  faster  than  it  will  increase  in  pure  water. 
As  the  value  C'h  for  the  actual  concentration  of  H  ions  decreases, 
and  the  value  C'h  for  the  concentration  of  H  ions  permitted  by 

the  equation  Ch=  — increases,  a    point   will    be    reached 

Cu 
where  C'h  =  Ch-     As  we  pass  this   point,   uric   acid   becomes 
the  strongest  acid    in  the  urine,  and,  in  fact,  we  have  proof  that 
at  37°  uric  acid  is  the  strongest  acid  in  the  urine. 

Tunicliffe  and  Rosenheim"^  took  a  set  of  flasks  containing 
100  cc.  of  urine  each,  and  containing  an  excess  of  undissolved 
uric  acid,  added  to  each  .2  gram  of  different  alkalies,  and  allowed 
the  solutions  to  remain  at  a  temperature  of  about  37°  until 
saturated.  The  alkalies  used  were  piperidine,  lysidin,  and  piper- 
azin.  These  authors  found  that  the  amount  of  uric  acid  dissolved 
by  each  was  proportional  to  the  solubility  of  their  respective 

1  F.  Tunicliffe  and  O.  Rosenheim.  Piperidine  as  a  Uric  Acid  Solvent,  a  Comparative 
Study.     Lancet,  July  23,  1898. 


Chemistry  87 

urates.  If  there  were  a  stronger  acid  than  uric  acid  present, 
we  should  have  the  condition  described  on  page  85,  that  is, 
these  alkalies  would  not  affect  the  solubility  of  the  uric  acid. 
On  addition  of  a  little  alkali,  the  H  ions  would  disappear  to  form 
HOH.  Immediately  new  H  ions  would  be  supplied  by  dissocia- 
tion of  the  stronger  acid  HA.  In  the  case  of  warm  urine,  how- 
ever, as  the  H  ions  disappear,  more  are  supplied  by  further 
dissociation  of  HU.  But  this  decreases  the  concentration  of  the 
undissociated  HU.  Therefore  more  uric  acid  goes  into  solution 
to  supply  this  deficiency. 

The  precipitation  of  sodium  acid  urate  takes  place  when  the 
value  Cne  X  Cu  exceeds  the  constant  K  X  CNaU,  where  CneU  is 
the  value  for  the  solubility  of  undissociated  sodium  acid  urate. 
(CNa  X  Cu  =  K  X  CNau).  Therefore,  either  a  high  concentration 
of  sodium  salts  or  a  large  amount  of  uric  acid  might  bring  about 
a  precipitation  of  sodium  urate.  We  can  see  a  reason,  therefore, 
for  a  precipitation  of  the  urate  in  alkaline  urine,  a  condition 
which  sometimes  occurs.  A  precipitation  of  both  uric  acid  and 
sodium  acid  urate,  such  as  we  often  have  in  urine,  will  occur 
when  the  concentration  of  Na  ions,  H  ions,  and  negative  U  ions  is 
such  that  the  values  for  the  solubility  products  of  both  the  uric 
acid  and  the  sodium  urate  are  exceeded. 

What  now  will  be  the  effect  of  alkali  on  a  urine  from  which 
uric  acid  precipitates  while  still  warm?  Obviously,  in  this 
case,  the  solubility  product  Ch  X  Cu  =  K  is  exceeded  even  in 
the  warm  urine.  Therefore  uric  acid  is  not  the  strongest  acid 
in  solution.  We  have  in  this  case  the  condition  usually  found  in 
cold  urine.  The  addition  of  a  little  alkali  will  not,  therefore, 
affect  the  solubility  of  the  uric  acid.  Addition  of  large  amounts 
of  alkali  will  have  some  effect  on  the  solubility  of  the  uric  acid. 

By  the  addition,  then,  of  alkali  to  a  normal  urine,  we  should 
increase  the  solubility  of  uric  acid  in  it  at  the  body  temperature, 
and  by  the  addition  of  considerable  quantities  of  alkali  to  a 
urine  from  which  uric  acid  precipitates  while  still  warm,  we 
should  expect  to  increase  its  power  of  dissolving  uric  acid  at 
the  body  temperature.  As  it  is  the  latter  case  with  which  we 
have  to  deal  in  practical  therapeutics,  we  should  for  the  best 
results  give  as  much  alkali  as  it  is  possible  to  give  without  making 
the  urine  alkaline. 

We  hope  to  determine  the  dissociation  constants 


88      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

K,  =  ChXChpo,  (^^  igo)  ^  K,  =  Ch^IChpo,  ^^^  3^0)  ^  ^3  ==  ^^XCu 

CH2PO4  CH0PO4  Chu 

at  37°),  and  to  study  the  "actual"  and  "potential"  acidity  of 
different  urines  at  18°  and  at  37°,  their  content  of  alkaline  and 
acid  sodium  phosphate,  and  uric  acid,  and  the  amount  of  uric 
acid  precipitated  on  cooling,  in  order  that  the  conditions  in 
urine  be  made  still  clearer,  and  that  we  may  be  able  to  predict 
quantitatively  the  effect  of  a  certain  amount  of  alkali  on  a  urine 
and  the  amount  of  uric  acid  which  will  precipitate  spontaneously 
on  cooling  from  the  chemical  composition  and  acidity  of  the  urine. 
There  is  no  reason  to  believe  that  the  precipitation  of  the 
acid  urate  of  sodium  or  ammonium  is  anything  more  than  a 
simple  precipitation  due  to  decreased  solubility  in  the  cool 
urine.  Of  course,  the  absence  of  conditions  which  change  the 
urate  to  uric  acid  influence  the  precipitation.  A  large  amount 
of  urate,  a  large  amount  of  sodium  salts  which  decrease  the 
dissociation  and  therefore  the  solubility  of  the  urate  of  sodium, 
and  small  amount  of  urine,  tend  to  bring  about  a  precipitation 
of  urate.  We  may  have,  too,  a  mixed  precipitate  of  urate  and 
uric  acid. 

Uric  Acid  in  the  Blood  and  Tissue  Fluids 

Garrod  ^  found  a  small  amount  of  uric  acid  in  the  watery  ex- 
tract of  evaporated  human  blood  by  precipitation  with  hydro- 
chloric acid.  Abeles  ^  found  it  in  blood  by  means  of  the  murexid 
test.  Petren^  thinks  it  is  normally  in  the  blood.  Neither  v. 
Jaksch^  nor  Klemperer^  could  find  uric  acid  in  normal  human 
blood. 

Uric  acid  has  been  found  in  the  blood  in  different  diseases. 
Garrod*^  has  found  it  in  gout,  Klemperer''  and  Magnus-Levy^ 
in  leukemia  and  nephritis,  v.  Jaksch  *  in  typhus,  malaria,  car- 
cinoma of  the  liver,  heart  diseases,  and  diseases  of  the  lungs  and 

1  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheumatism,  and  Bright's  Disease.     Med.  Chir.  Trans.,  Bd.  XXXI,  83,  1848. 

2  Abeles.     From  Schreiber.     Ueber  Harnsaure.     Stuttgart,    1899,   p.   26. 

3  P^tren.     From  Schreiber.     Ueber  die  Harnsaure.     Stuttgart,  1899,  p.  26. 

*  R.  V.  Jaksch.     Ueber  Uricacidamie.      Deutsche  Med.  Wochenschrift,  16,  33  (1890). 

5  Klemperer.     Untersuchungen  iiber  Gicht  und  harnsaure  Nierensteine.     Berl.,  96,  3. 

6  Garrod.     The  Nature  and  Treatment  of  Gout. 
^  Klemperer.  Gicht,   3. 

8  A.  Magnus-Levy.  Ueber  den  Stoffwechsel  bei  acuter  und  chronischer  Leukamie. 
A^irchow's  Archiv,   152,   107   (1898). 


Chemistry  89 

pleura.  Salomon  ^  and  Petren  ^  have  found  it  in  the  blood  in 
pneumonia  and  angemia.  Petren^  has  found  it  in  the  blood  in  a 
case  of  hysterical  vomiting  and  in  a  case  of  gonorrheal  rheuma- 
tism. In  anaemia,  Boucheron  ^  has  found  uric  acid  in  the  saliva 
and  in  the  mucus  of  the  nose,  pharynx,  bronchi,  uterus,  vagina, 
stomach,  and  fluids  of  the  eye.  Colosanti*  found  it  in  the 
vomitus  in  a  case  of  hysterical  oligurea. 

It  has  been  found  by  v.  Jaksch^  and  by  Pickardt"  in  transu- 
dates and  exudates,  especially  in  nephritis,  and  by  Naunyn^  in 
pleuritic  and  other  fluid  exudates.  We  have,  of  course,  the  uric 
acid  concretions  in  gout,  the  uric  acid  stones,  and  the  uric  acid 
infarcts  in  addition. 

Cloetta^  found  uric  acid  in  the  human  spleen,  lungs,  liver, 
and  brain,  and  Abeles^  in  the  human  spleen,  liver,  cartilage,  and 
connective  tissue.  Abeles  found  in  the  liver  and  muscles  of  dogs 
and  horses,  likewise,  a  very  small  trace  of  uric  acid,  but  found 
none  in  their  blood.  Meissner  ^*'  found  it  in  the  blood  of  dogs, 
but  Liitze "  could  not  find  it.  v.  Jaksch,^  Schroder ,^^  Petren,^ 
could  not  find  it  in  the  blood  of  rabbits,  rams,  cattle,  swine,  or 
horses.  Garrod,^^  too,  could  not  find  it  in  rams'  blood.  Nencki 
and  Kowarski  ^*  could  find  no  uric  acid  in  the  muscles  of 
mammals. 

We  do  not  know  at  the  present  time  in  what  condition  the  uric 

1  G.  Salomon.  Ueber  die  Verbreitung  und  Entstehung  von  Hypoxanthin  und  Mileh- 
saure  im  thierischen  Organisraus.     Zeitschr.  fiir  physiol.  Chem.,  2,  65  (1878). 

2  K.  Petren.  Ueber  das  Vorkommen  von  Harnsaure  im  Blute  bei  Menschen  und  Sau- 
gethiere.     Arch,  fiir  exp.  Path.  u.  Pharm.,  41,  265  (1898). 

2  Boucheron.  De  I'acide  urique  dans  la  salive  et  dans  de  mucus  nasal  pharinge,  bron- 
chique,  utero-vaginal.     Comptes  rendus,  100,  1308. 

•*  G.  Colosanti.  Ueber  das  Erbrechen  bei  Oligurie.  Moleschott's  Unters.  z.  Natur- 
lehre  d.  Menschen.,  14,  Separatabde,  10  p. 

5  V.  Jaksch.     Ueber  Uricacidamie.     Deutsche  Med.  Wochenschrift,   16,  33  (1890). 

s  M.  Pickardt.  Zur  Kenntniss  der  Chemie  pathologischer  Ergiisse.  Berl.  klin.  Woch- 
enschrift, 34,  39  (1897). 

'  Naunyn.     Arch,  fiir  Anat.  u.  Physiol.,   1864,  188. 

*A.  Cloetta.  Ueber  das  Vorkommen  von  Inosit,  Harnsaure,  etc.,  in  thierischen  Kor- 
per.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  99,  289  (1856). 

^Abeles.     From  Schreiber.     Ueber  Harnsaure.,     Stuttgart,   1899,  p.  26. 

'"  G.  Meissner.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  thierischen  Organismus. 
Zeitschr.  fiir  rat.  Med.,  Ill,  31,  144  (1868). 

1'  Liitze  (from  Klemperer,  Gicht). 

12  W.  V.  Schroder.  Ueber  den  Harnsauregehalt  des  Blutes  und  der  Leber  der  Vogel* 
C.   Ludwig'sche   Festschrift,  Leipzig,  1887. 

'3  Garrod  (see  Petren).  Ueber  das  Vorkommen  von  Harnsaure  im  Blute  bei  Menschen 
und  Siiugethiere.     Arch,  fiir  exp.  Path.  u.  Pharm.,  41,  265  (1898). 

1^  Nencki  und  Kowarski.  Ueber  das  Vorkommen  von  Harnstoff  im  Muskel  der  Sau- 
gethiere.     Arch,  fur  exp.  Path.  u.  Pharm.,  36,  395  (1895). 


90      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

acid  exists  in  the  blood.  Wittich^  stated  that  it  is  not  found 
free,  but  as  a  salt,  and  probably  the  neutral  urate,  since  this 
is  the  most  soluble  of  the  common  urates.  Carbon  dioxide  will 
precipitate  the  less  soluble  acid  urate  from  a  solution  of  neutral 
urate.  The  carbon  dioxide  in  the  tissues  may  cause  the  acid 
urate  to  precipitate  from  the  blood  in  this  way  in  gout,  according 
to  Wittich.^  Again,  the  tissues  may  withdraw  some  of  the  base 
from  the  neutral  urate,  forming  thereby  alkali  albuminate,  and 
leaving  the  insoluble  acid  urate.  Pawlinoff^  thinks  that  the 
hypotheses  of  Wittich  may  be  correct. 

The  views  of  Wittich  and  Pawlinoff  do  not  seem  to  have  been 
questioned  until  Roberts  ^  called  attention  to  the  fact  that  neu- 
tral sodium  urate  cannot  exist  in  a  solution  that  contains  no 
free  sodium  hydroxide,  and  that  it  cannot  exist  in  a  solution 
containing  carbonic  acid.  Neutral  sodium  urate  then  can 
certainly  not  exist  in  the  blood. 

The  view  of  Roberts  that  uric  acid  circulates  in  the  blood  as 
sodium  quadriurate  is  an  hypothesis  based  simply  on  the  fact 
that  Roberts  and  Jones  believed  that  quadriurates  exist.  It 
has  been  shown,  however,  that  there  is  no  reason  to  believe  that 
such  compounds  exist. 

We  have  seen  that  it  has  not  been  possible  to  prepare  a  double 
compound  of  sodium  acid  urate  and  alkaline  sodium  phosphate. 
Hence  the  view  of  Pfeiffer  *  that  the  uric  acid  circulates  in  the 
blood  in  the  form  of  a  double  salt  of  acid  urate  and  alkaline  phos- 
phate of  sodium  has  no  foundation  in  fact. 

Mordhorst^  believed  that  the  uric  acid  is  not  dissolved  in 
the  blood,  but  is  suspended  in  a  finely  divided  condition  loosely 
combined  with  varying  amounts  of  sodium.  This  is  the  condition 
of  the  so-called  "  kugel  "  urates,  according  to  him.  Mordhorst's 
theory  is,  however,  based  on  a  fallacy.  It  has  been  shown  that 
the  "  kugel  "  urates,  are  definite  chemical  compounds.    His  later 

1 V.  Wittich.  Ueber  Harnsecretion  und  AlbumiQurie.  Virchow's  Archiv  fiir  Path. 
Anat.,  10,  325  (1856). 

2  C.  PawUnoff.  Die  Bildungsstatte  der  Harnsaure  im  Organismus.  Virchow's  Archiv 
fiir  Pamr7Siirr62,  57  (1875). 

3  W.  Roberts.  On  the  Chemistry  and  Therapeutics  of  Acid  Uric  Gravel  and  Gout. 
(Croonian  Lecture  for   1892.)     Lancet,   1892. 

*  E.  Pfeiffer.  Ueber  Harnsaureverbindungen  beim  Menschen.  Berl.  kUn.  Wochen- 
schrift,  STTOTS  (1894). 

5  C.  Mordhorst.  Die  Entstehung  und  Aufiosung  der  Harnsaureverbindungen 
ausserhalb  und  innerhalb  des  menschhchen  Korpers.  Zeitschr.  fiir  klin.  Med.,  32,  65 
(1897). 


Chemistry  91 

view/  that  the  "  kugel  "  urates  are  compounds  of  sodium  hy- 
droxide and  uric  acid,  are,  as  we  have  seen,  erroneous. 

We  have  no  reason  to  beheve  that  the  uric  acid  exists  in  the 
blood  and  tissues  in  the  form  of  a  salt.  Until  recently  it  has  been 
very  generally  believed  that  uric  acid  is  destroyed  in  the  organism, 
and  cannot  exist  in  the  blood.  To  explain  the  presence  of  uric 
acid  in  the  urine  under  these  circumstances,  von  Noorden  offered 
the  suggestion  that  the  uric  acid  might  be  united  in  some  organic 
compound  in  some  such  way  that  it  was  not  capable  of  being  oxi- 
dized to  urea,  and  that  uric  acid  is  set  free  only  in  the  kidneys. 
Goto^  has  prepared  soluble  compounds  of  uric  acid  with  nucleic 
acid  and  thymic  acid  from  which  the  uric  acid  is  not  precipitated 
by  hydrochloric  acid  or  the  other  common  uric  acid  precipitants. 
Minkowski,^  in  a  discussion  of  one  of  His's  articles,  stated  that 
he  had  prepared  the  same  compounds.  His  *  has  prepared  a 
similar  compound  of  uric  acid  and  formaldehyde,  and  he  thinks 
that  there  are  undoubtedly  a  large  number  of  bodies  which  com- 
bine organically  in  this  way  with  uric  acid.  If,  as  His  suggests, 
the  uric  acid  in  the  body  is  combined  not  as  a  salt,  but  organi- 
cally, in  some  such  way  as  with  thymic  acid,  it  may  be  present 
in  much  higher  concentration  than  we  suspect,  for  our  usual 
tests  do  not  show  its  existence  when  it  is  combined  in  this  way. 
Schmoll,^  too,  has  suggested  that  uric  acid  circulates  in  the  blood 
in  combination  with  thymic  acid,  but  has  not  offered  any  good 
evidence  for  his  view. 

1  C.  Mordhorst.  Wirkimgsweise  des  kohlensauren  tind  des  salicylsauren  Natrons  bei 
Gicht,  Rheumatismus,  etc.     Centralbl.  fur  innere  Medizin,  18,  409  (1898). 

-  JI.  Goto.  Ueber  die  Losung  der  Harnsaure  diirch  Nucleinsiiure  und  Thjrminsaure. 
Zeitschr.  fur  physiol.  Chem.,  30,  473  (1900). 

3  Minkowski's  discussion  of  Ilis's  article.  W.  His.  Das  Verhalten  des  Harnsaure  im 
thierischen  Organismus.  Verhandl.  des  17t  Kongr.  ftir  innere  Medizin,  Wiesbaden,  315 
(1899). 

*  W.  His.  Schicksal  und  Wirkungen  des  sauren  hamsauren  Natrons  in  Bauch  und 
Gelenkhohle  des  Kaninchens.     Deutsche  Archiv   fiir  klin.  Medizin,  67,  81  (1900). 

5  E.  SchmoU.  Sur  la  Formation  de  I'acide  urique  dans  la  goutte  et  les  causes  de  sa 
precipitation  dans  les  tissus.     Arch.  gen.  de  Med.,  2,  2433  (1904). 


92      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 


II.  PHysiolo^y  of  Uric  Acid 


Uric  Acid  in  Birds 

A  STUDY  of  the  nitrogenous  metabolism  of  birds  is  of  considerable 
importance  for  a  correct  understanding  of  the  metabolism  of 
uric  acid  in  mammals.  Although  it  has  been  shown  that  uric 
acid  in  birds  is  analogous  to  urea  in  mammals  in  that  it  is  the 
chief  end  product  of  their  nitrogenous  metabolism,  yet  Wiener/, 
as  a  result  of  his  work  on  the  subject,  seems  to  think  that  the 
formation  of  uric  acid  in  birds  and  in  mammals  takes  place  in 
the  same  way,  and  that  the  difference  lies  in  the  relative  quanti- 
ties formed  by  each  method  in  the  two  classes  of  animals.  There 
is  some  objection  to  this  theory,  however,  as  we  shall  see  later. 

In  birds,  and  in  certain  reptiles,  the  chief  end  product  of  ni- 
trogenous metabolism  is  uric  acid.  It  is  formed  by  oxidation 
of  proteid,  and  a  generation  or  so  ago  —  and  even  more  recently  — 
the  uric  acid  in  mammals  was  very  generally  supposed  by  analogy 
to  come  from  proteid.  Since  outside  the  body  urea  can  be  ob- 
tained by  oxidation  of  uric  acid,  the  formation  of  uric  acid  in 
mammals  was  supposed  to  be  due  to  incomplete  oxidation  of 
proteid.  All  theory  and  experiment  upon  the  subject  was  based 
upon  this  view,  which  we  know  now  to  be  incorrect. 

Uric  acid  was  first  found  in  the  excrement  of  birds  by  Four- 
croy  and  Vauquelin,^  and  in  that  of  serpents  by  Prout.^  Wollas- 
ton  ■*  found  calcium  urate  and  uric  acid  in  the  urine  of  different 
birds.  V.  Wittich^  showed  that  uric  acid  concretions  were 
formed  in  the  epithelium  cells  of  the  kidney,  and  excretion  took 

'■  H,.— WieaeP:  Ueber  synthetische  Bildung  der  Harnsaure  im  Tierkorper.  Verhandl. 
des  IQt  Kongr.  fiir  innere  Medizin,  Wiesbaden,  383  (1901),  and  Beitrage  zur  chem- 
isch.  Physiol,  u.  Pathol.,  242  (1902). 

2  Fourcroy  and  Vauquelin.  Sur  le  guano,  ou  sur  I'engrais  naturel  des  ilots  de  la  mer 
du  Sud,  pres  des  cotes  du  Perou.     Annales  de  Chimie,  56,  258  (1805). 

3  Thomson.  Analysis  of  the  Excrements  of  the  Boa  Constrictor.  Annals  of  Philoso- 
phy, 5,  413  (1815). 

*Wollaston.     Annales  de  Chimie,  76,  31  (1810). 

■'  V.  Wittich.     Harnsauresecretion  und  Albuminurie.     Virchow's  Archiv,  10,  325  (1856). 


Physiology  93 

place  as  these  cells  degenerated.  Coindet^  and  Davy^  thought 
that  the  uric  acid  in  bird  excrement  is  combined  as  ammonium 
urate,,  and  Cap  and  Henry^  that  it  is  combined  with  urea  which 
Coindet^  had  shown  to  exist  in  small  quantities  in  the  excrement. 
Meissner,*  and  later  v.  Knierem,^  proved  experimentally  that 
the  excrement  consists  chiefly  of  free  uric  acid  and  not  of  a  com- 
pound of  uric  acid.  Some  urates  were  found.  According  to 
Milroy,"  small  amounts  of  purin  bases  are  found  in  birds'  urine. 

The  Nitrogenous  Metabolism  in  Birds 

Both  Coindet^  and  Zalesky^  found  urea  in  the  excrement  of 
birds,  but  Cech^  found  that  if  urea  were  administered  to  birds, 
it  did  not  reappear  in  the  urine.  This  was  explained  by  Meyer 
and  Jaffe,^  by  Cech,^  and  by  Meyer.^°  These  authors  showed 
that  the  administration  of  urea  to  birds  does  not  increase  the 
excretion  of  urea,  but  does  increase  the  excretion  of  uric  acid. 
Further,  according  to  v.  Knierem,^^  amido  acids  which  are  some- 
times obtained  as  decomposition  products  of  proteid,  and  which, 
when  administered  to  mammals,  increase  the  excretion  of  urea,  in 
birds  are  changed  to  uric  acid.  According  to  this  author,  ammo- 
nium salts  do  not  change  to  uric  acid  in  the  organism  of  birds. 
V.  Schroder^^  has  showm,  however,  that  only  ammonium  chloride 

1  Coindet.  Considerations  sur  la  production  de  I'acide  urique.  Bibliotheque  univer" 
selle,  T.  XXX,  p.  495.     Geneva  (1825). 

2  Davy.     Physiological  Researches,  p.  191.     London  and  Edinburgh  (1863). 

3  Cap  und  Henry.  Ucber  milchsauren  Harnstoff,  nebst  Bemerkungen  liber  Harnstoff 
und  Milchsaure  und  ihre  Salze  iiberhaupt,  so  wie  iiber  den  Zustand  des  Harnstoffs  im 
Urine.     J.  de  Pharm.,  133  (1839). 

^  G.  Meissner.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  thierischen  Organismus. 
Zeitsclir.  fiir  rationelle  Med.,  Ill  Reihe,  31,  144  (1868). 

^  W.  V.  Knierem.  Verhalten  der  im  Saugethierkorper  als  Vorstufen  des  Harnstoffs 
erkannten  Verbindungen  zum  Organismus  der  Hiihner.  Zeitschr.  fiir  Biol.,  13,  36 
(1877). 

8  I\__MilrciK_  The  Formation  of  Uric  Acids  in  Birds.  Journ.  of  Physiol.,  30,  47 
(1903). 

'  Zalesky.  Untersuchungen  iiber  den  uramischen  Prozess  und  die  Funktion  der  Nieren. 
ToEingen,'  i§65. 

8  C.  O.  Cech.  Ueber  das  Verhalten  des  Taurins  in  Organismus  der  Vogel.  Ber.  der 
Dtsch.  chem.  GeselL,  10,  1461  (1877). 

8  H.  Meyer  und  W.  Jaffe..  Entstehung  der  Harnsaure  im  Organismus  der  Vogel.  Ber. 
der  Dtsch.  chem.  Gesell,  10,  1930  (1877). 

^H.  Meyer.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  Organismus  der  Hiihner. 
Dissertation,  Konigsberg,  1S77. 

I'W.  V.  Knierem.  Verhalten  der  im  Saugethierkorper  als  Vorstufen  des  Harnstoffs 
erkannten  Verbindungen  zum  Organismus  der  Hiihner.     Zeitschr.  fiir  Biol.,  13,  36  (1877). 

"  W.  V.  Schroder.  Ueber  die  Verwandlung  des  Ammoniaks  in  Harnsaure  im  Organis- 
mus des  Huhns." Zeitschr.  fur  physiol.  Chem.,  2,  228  (1878). 


94    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

and  sulphate  and  those  ammonium  salts  which  are  easily  changed 
into  the  chloride  of  sulphate  are  excreted  unchanged,  and  that 
ammonium  carbonate  and  those  salts  of  ammonia  with  organic 
acids  which  change  to  ammonium  carbonate  on  oxidation  are 
excreted  as  uric  acid.  This  author  expressed  the  view  that  in 
this  case  we  have  a  synthesis  of  uric  acid. 

These  experiments  which  showed  that  urea,  ammonium  com- 
pounds, and  amido  acids  are  changed  to  uric  acid  in  birds  seemed 
to  indicate  some  analogy  between  uric  acid  in  birds  and  urea  in 
mammals.  AVith  the  exception  of  the  article  of  Frankel  and 
Rohmann,^  who  found  that  in  hens  suffering  from  phosphorus 
poisoning  the  excretion  of  uric  acid  is  increased,  and  who  think 
that  this  is  due  to  defective  oxidation  of  proteid,  very  little  refer- 
ence is  made  during  the  last  twenty-five  years  to  the  formation 
of  uric  acid  in  birds  as  a  process  of  defective  oxidation.  The 
analogy  between  the  formation  of  urea  in  mammals  and  uric 
acid  in  birds  was  strongly  confirmed  by  Cazeneuve,^  who  found 
that  the  relative  amounts  of  urea,  uric  acid  and  ammonia  ex- 
creted were  the  same  whether  the  birds  have  an  excessive  or  a 
deficient  amount  of  oxygen,  and  that  the  absolute  amounts  of 
each  were  dependent  upon  the  quantity  of  nitrogenous  food 
taken.  Further  confirmation  of  this  analogy  was  given  by 
Schimanski,^  who  showed  that  like  the  urea  in  animals'  urine,  so 
the  uric  acid  in  birds'  urine  rapidly  increases  toward  the  end  in 
inanition. 

Organ  of  Formation  of  Uric  Acid  in  Birds 

Strahl  and  Lieberkiihn^  analyzed  the  blood  of  doves,  hens, 
and  snakes,  and  found  it  free  from  uric  acid.  He  concluded, 
therefore,  that  the  uric  acid  is  formed  in  the  kidneys.  Zalesky  ^ 
confirmed  the  discovery  of  Strahl  and  Lieberkiihn.  He  found, 
also,  that  after    tying  the  ureters  of    snakes,  geese,  and   hens, 

1  A.  Frankel  und  F.  Rohmann.  Fhosphorvergiftung  bei  Huhnern.  Zeitschr.  fiir 
physiol.  Chem.,  4,  439  (1880). 

2  P.  Cazeneuve.  Sur  I'excretion  de  I'acide  urique  chez  les  oiseaux.  Compte  rend,  de 
soci^t.  bioL,  93,  1155  (1881). 

3  FI.  Schimanski.  Der  Inanitions  und  T'ieberstoffwechsel  der  Hiihner.  Zeitschr.  fiir 
physiol.  Chem.,  3,  396  (1889). 

*  Strahl  und  Lieberkiihn.  Harnsaure  im  Blute  und  einige  neue  Bestandtheile  des 
Urins.  Berlin  (1848).  Also  Jahresber,  iiber  die  Fortschritte  in  die  gesammten  Medicin 
(1848). 

^  Zalesky.  Untersuchungen  iiber  den  uramischen  Prozess  und  die  Funktion  der  Nieren. 
Tiibingen,  1865. 


Physiology  95 

concretions  of  uric  acid  appear  in  the  different  organs  of  the 
animal.  These  concretions  appear  first  in  the  kidneys  and 
later  in  the  other  organs.  When  the  kidneys  are  extirpated  in 
snakes,  or  cut  out  of  the  circulation  by  tying  off  the  blood  supply 
in  birds,  the  uric  acid  concretions  do  not  appear,  according  to 
Zalesky.  These  facts  seemed  to  indicate  the  kidneys  as  the  or- 
gans in  which  uric  acid  is  formed.  Chrzonszczewsky^  likewise 
found  uric  acid  concretions  in  the  various  organs  and  tissues 
of  birds  after  tying  the  ureters.  This  author  considered  the 
connective  tissue  the  source  of  uric  acid  on  account  of  the  fact 
that  the  uric  acid  appears  in  the  nucleus  of  the  connective  tissue 
cells  before  it  appears  at  any  place  but  the  kidneys.  From  the 
nucleus  the  concretions  spread  to  the  body  of  the  cell,  then  to 
the  cell  processes,  and  finally  into  the  lymphatic  system. 

Meissner,^  and  later  Pawlinoff,^  found  that  the  blood  analyses 
of  Strahl  and  Lieberkiihn  and  Zalesky  were  faulty,  and  that  by 
working  with  sufficient  quantities  uric  acid  can  be  found  normally 
in  the  blood  and  organs  of  snakes  and  birds.  Further,  Pawlinoff 
found  that  after  nephrotomy  is  properly  performed  on  birds, 
uric  acid  concretions  appear  in  the  various  organs  and  tissues 
just  as  they  do  after  tying  the  ureters,  v.  Schroder  ^  showed 
that  uric  acid  is  present  in  the  blood  of  nephrotomized  birds  and 
snakes,  and  that  after  kidney  extirpation  uric  acid  concretions 
are  found  in  the  various  organs  and  tissues  of  the  snake  just  as 
they  are  after  tying  the  ureters.  Colasanti  ^  found  that  the  con- 
cretions formed  in  the  various  organs  after  tying  the  ureters  of 
hens  are  urates,  those  in  the  ureters,  uric  acid.  The  kidneys, 
therefore,  are  not  the  source  of  uric  acid  in  snakes  or  in  birds. 

Meissner  found  uric  acid  in  especially  large  quantities  in  the 
liver  of  normal  birds,  although  Stokvis  ^  had  previously  missed 

1  N.  Chrzonszczewsky.  Ueber  den  Ursprung  der  Lyiuphgefasse.  Virchow's  Archiv,  35, 
174  11866).  ' 

2  G«»Jtf©iee»«ri  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  thierisclien  Organismus. 
Zeitschr.  fur  rationelle  Med.,  Ill  Reihe,  31,  144  (1868). 

^  Tj;  PawliiirijT  Die  Bildungsstatte  der  Harnsaure  im  Organismus.  Virchow's  Archiv, 
62,  57  (1875). 

^  W.  V.  Schroder.  Ueber  die  Bildungsstatte  der  Harnsaure  im  Organismus.  Arch. 
f.TAnat''u7  Physiol.,  1880.     Suppl.  Bd.,  p.  113. 

"  G.  Cola.saBJa»»  Ricerche  sperimentali  sulla  formazione  dell'  acido  mico.  Giornale 
di  medic,  mihtar,  25,  1  (1881). 

Also,  Experimental  Untersuchungen  iiber  die  Bildung  der  Harnsaure.  Moleschott's 
Unters.,  13,  75  (1881). 

•>  Stokvis.  Archiv.  fiir  die  hollandische  Beitrage  zur  Natur  und  Heilkunde.  II  Serie, 
Bd.   2,   260^(1860). 


96      The  Chemistry  J  Physiology ,  and  Pathology  of  Uric  Acid 

it  in  the  liver  of  the  dove.  Meissner,  therefore,  beheved  the 
liver  the  source  of  uric  acid.  Pawlinoff  thought  that  the  concre- 
tions are  more  nearly  related  to  the  blood,  and  that  they  are 
formed  at  those  places  where  there  is  the  least  resistance  to  their 
separation  from  the  blood.  The  work  of  Minkowski  and  others, 
which  shows  the  liver  to  be  the  organ  concerned  with  the  forma- 
tion of  uric  acid  in  birds,  will  be  considered  in  the  next  section. 

Uric  Acid  Formed  by  Synthesis  in  Birds 

Perhaps  the  most  important  work  on  the  uric  acid  is  that  of 
Minkowski.^  He  found  that  of  the  total  nitrogen  found  in  the 
urine  of  normal  geese,  60  to  70  per  cent  is  in  the  form  of  uric 
acid,  9  to  18  per  cent  in  the  form  of  ammonia,  and  3  to  4  per  cent 
in  the  form  of  urea.  In  the  urine  of  geese  whose  livers  have  been 
extirpated,  50  to  60  per  cent  of  the  nitrogen  is  in  the  form  of 
ammonia  and  very  little  in  the  form  of  uric  acid.  The  amount  of 
urea  in  the  urine  is  not  changed  by  liver  extirpation. 

Ammonium  compounds  or  amido  acids  administered  to  geese 
with  liver  extirpated  appeared  in  the  urine  as  ammonia.  Urea 
passed  through  the  organism  unchanged.  This  indicated  the 
liver  as  the  organ  in  which  uric  acid  is  synthesized. 

Minkowski  noted  that  a  synthesis  of  uric  acid  from  ammonia 
and  carbon  dioxide,  which  at  that  time  physiologists  considered 
probable  in  birds,  cannot  take  place  unless  a  considerable  reduc- 
tion takes  place  at  the  same  time,  and  since  oxidation  and  not 
reduction  processes  characterize  the  animal  organism,  he  thought 
it  much  more  likely  that  the  ammonia  combined  with  some 
other  compound  containing  a  relatively  larger  amount  of  carbon 
and  smaller  amount  of  oxygen  than  carbon  dioxide.  In  the  urine 
of  geese  with  extirpated  liver  he  found  lactic  acid  a  body  answer- 
ing this  description.  It  may  be  mentioned  that  Berlinblau^ 
has  found  lactic  acid  a  constant  constituent  of  normal  blood. 

Milroy^  has  observed  that  galvanic  stimulation  of  the  bird's 
liver  aids  the  synthesis  of  uric  acid. 

In  normal  geese  urine  we  do  not  find  lactic  acid,  but  in  the  urine 

1 0.  Minkowski.  Ueber  den  Einfluss  der  Leberextirpation  auf  dem  Stoffwechsel. 
Arch,  fiir  exp.  Path.  u.  Pharm.,  21,  40  (1886). 

2  Berlinblau.  Ueber  das  Vorkommen  der  Milchsaure  im  Blute  und  ihre  Entstehung 
im  Organismus.     Arch,  fiir  exp.  Path.  u.  Pharm.,  23,  p.  333  (1887). 

3  T.  Milroy.  The  Formation  of  Uric  Acids  in  Birds.  Journ.  of  Physiol.,  30,  47 
(1903). 


Physiology  97 

of  geese  with  extirpated  liver  more  than  half  the  non-volatile 
portion  consists  of  lactic  acid.  The  ammonia  and  lactic  acid 
are  probably  combined  to  form  ammonia  lactate,  for  the  quan- 
tities are  about  in  the  ratio  to  form  the  salt.  The  highest  amount 
of  lactic  acid  was  found  after  a  meat  diet  and  in  starvation,  and 
the  lowest  amount  on  a  carbohydrate  diet.  The  lactic  acid, 
therefore,  proVjably  comes  from  proteid. 

In  brief,  then,  the  end  product  of  proteid  metabolism  in  normal 
geese  is  chiefly  uric  acid,  while  in  geese  with  extirpated  liver  it 
is  chiefly  ammonium  lactate.  From  these  experiments,  Min- 
kowski concluded  that  uric  acid  is  synthesized  in  the  liver  in  geese 
from  ammonia  and  sarco-lactic  acid.  Horbaczewski  *  agrees  with 
him  and  thinks  that  the  artificial  synthesis  of  uric  acid  from  urea 
and  the  amide  of  trichlorlactic  acid  ^  strengthens  this  assumption. 
About  the  same  time,  v.  Schroder^  found  that  there  is  very  little 
uric  acid  in  the  blood  of  birds,  but  much  larger  quantities,  six  to 
fourteen  times  as  much,  in  the  liver.  This  alone,  however,  does 
not  indicate  that  uric  acid  is  formed  in  the  liver. 

Hoppe-Seyler  *  suggested  that  the  appearance  of  lactic  acid 
in  birds'  urine  after  liver  extirpation  might  be  due  to  deficient 
oxidation  on  account  of  disturbance  of  the  respiratory  system, 
since  Araki^  and  Zillessen^  have  found  it  in  the  urine  of  birds 
which  suffered  from  lack  of  oxygen. 

In  a  later  article,^  Minkowski  answered  the  objection  of  Hoppe- 
Seyler  by  showing  that  extirpation  of  the  liver  is  not  necessary 
to  produce  ammonium  lactate  acid  in  the  urine.  This  is  brought 
about  by  simply  tying  the  blood  vessels  entering  the  liver.  If, 
however,  but  a  single  branch  of  an  entering  blood  vessel  be  left 
open  the  uric  acid  synthesis  can  take  place.     Minkowski  thus 

'  Horbaczewski.  Weitere  synthetische  Versuche  iiber  die  Konstitution  der  Harnsaure 
und  Bemerkungen  iiber  die  Entstehung  derselben  in  Thierkorper.  Monatshefte  fiir 
Chem.,  8,  584  (1887). 

2  J.  Horbaczewski.  Ueber  eine  neue  Synthese  und  die  Constitution  der  Harnsaure. 
Monatshefte  fur  Chem.,  201  (1887). 

^  V.  Schroder.  Ueber  den  Harnsauregehalt  des  Blutes  und  der  Leber  der  Vogel.  Bei- 
trage  zu  Physiol.     Festschr.  f.  C.  Ludwig,  p.  89.     Leipzig,  1887. 

^  Hoppe-Seyler.  Beitrage  ziir  Kenntniss  des  Stoffwechsels  bei  Sauerstoflmangel. 
Festschr.  zu  R.  Virchow's  70  Geburtstage. 

^  T.  Araki.  Ueber  die  Bildung  von  Milchsaure  und  Glycose  im  Organismus  bei  Sauer- 
stoffmangel.     Zeitschr.  fiir  physiol.  Chem.,  5,  546  (1891). 

6  Zillessen.  Ueber  die  Bildung  von  Milchsaure  und  Glykose  in  den  Organen  bei  ges- 
torter  Circulation  und  bei  der  Blausaurevergiftung.  Zeitschr.  fiir  physiol.  Chem.,  5,  387 
(1891). 

^  Minkowski.  Ueber  die  Ursachen  der  Milchsaureauscheidung  nach  der  Leberextir- 
pation.     Arch,  fiir    exp.  Path.  u.  Pharmak.,  31,  214  (1893). 


98      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

showed  that  the  disturbance  of  function  was  due  solely  to  the 
absence  of  the  liver. 

A  second  objection  to  Minkowski's  conclusions  was  raised  by 
Bunge/  who  suggested  that  the  primary  disturbance  in  liver 
extirpation  was  the  excretion  of  lactic  acid,  and  that  the  excre- 
tion of  nitrogen  in  the  form  of  ammonia  was  caused,  as  in  acid 
intoxication,  by  a  demand  for  alkali  to  neutralize  the  acid.  The 
lack  of  uric  acid  formation  would  then  be  but  a  secondary  dis- 
turbance. 

Lang  ^  and  Kowalewski  and  Salaskin  ^  showed  that  administra- 
tion of  sodium  bicarbonate,  which  was  given  in  order  to  supply 
a  base  for  neutralization  of  the  acid,  lowered  somewhat  the  am- 
monia in  the  urine  of  birds  with  extirpated  liver,  but  did  not 
increase  the  amount  of  uric  acid,  and  Milroy  ^  has  shown  that 
the  administration  of  a  mineral  acid  in  doses  smaller  than  those 
which  result  in  acid  poisoning  diminishes  the  transformation 
of  ammonium  salts  into  uric  acid.  This  showed  that  a  part  of 
the  ammonia  is  taken  to  neutralize  the  acid,  but  apparently  this 
ammonia  nitrogen  is  not  taken  at  the  expense  of  the  uric  acid 
nitrogen.  Minkowski^  found  in  fact  that  the  ammonia  of 
normal  birds'  urine,  which  is  usually  acid,  was  partly  used  to 
neutralize  the  acid  present,  for  by  administration  of  alkali  we 
could  decrease  the  amount  present.  Lang^  also  repeated  and  con- 
firmed the  experiments  of  Minkowski  on  geese  with  extirpated 
livers. 

Stadthagen**  stated  that-  perhaps  only  certain  antecedents  of 
uric  acid  are  formed  in  the  liver  from  ammonia,  and  that  perhaps 
some  other  organ,  as,  for  example,  the  kidney,  forms  the  uric 
acid.  This  idea  was  shown  to  be  wrong  by  Kowalewski  and  Sala- 
skin ^  who  furnished  the  final  proof  that  uric  acid  can  be  synthe- 
sized in  the  liver  from  ammonium  lactate,  and  showed  that  if 

1  G.  Bunge.  Lehrbuch  der  physiologischen  und  pathologischen  Chemie.  4th  Aufl., 
338.     Leipzig  (1898). 

2  S.  Lang.  Ueber  die  Stickstoffausscheidung  nach  Leberextirpation.  Zeitschr.  physiol., 
Chem.,  32,  320   (1901). 

3  K.  Kowalewski  und  S.  Salaskin.  Ueber  die  Bildung  von  Harnsaure  in  der  Leber  der 
Vogel.'    Zeitschr.   fur  physiol.   Chem.,   33,   210    (1901). 

*  T.  Milroy.  The  Formation  of  Uric  Acid  in  Birds.  Jour,  of  Physiol.  Chem.,  30,  47  (1903). 
5  O.    Minkowski.     Ueber    den    Einfluss    der    Ijeberextirpation    auf    dem    Stoffwechsel. 
Arch,  fur  exp.  Path.  u.  Pharmak.,  21,  89  (1886). 

1  f"  M.  Stadthagen.  Ueber  das  Vorkommen  von  Harnsaure  in  verschiedenen  thierischen 
Organen,  ihr  Verhalten  bei  Leukamie  und  die  Frage  ihrer  Enstehung  aus  den  Stickstofi- 
basen.     Virchow's  Archiv,  109,  390  (1887). 


Physiology 


99 


blood  containing  ammonium  lactate  be  passed  through  an  isolated 
goose  liver  the  ammonium  lactate  is  changed  to  uric  acid. 
Since  uric  acid 


NH  — CO 


O       C  — NH 


NH  — C— NH/ 


CO 


is  a  diureide,  that  is,  a  derivative  of  two  molecules  of  urea 
and  a  non-nitrogenous  body,  it  seems  possible  that  ammonia 
may  be  changed  first  to  urea  and  then  b}^  combination  with  a 
non-nitrogenous  body  to  uric  acid.  At  any  rate  it  is  known 
that  from  urea  and  certain  acids  we  can  synthesize  uric  acid  in 
birds. 

Wiener*  showed  that  although  when  urea  is  fed  to  birds  it  is 
excreted  as  uric  acid,  yet  when  it  is  injected  in  large  quantities 
directly  into  the  arteries  most  of  it  is  excreted  unchanged.  He 
believes  that  the  explanation  is  that  the  large  quantity  of  urea 
suddenly  put  into  the  S3^stem  is  excreted  before  it  can  obtain 
sufficient  of  the  non-nitrogenous  compound  necessary  to  unite 
with  it  to  form  uric  acid.  He  found  that  if  glycerin  or  the  ali- 
phatic oxy-,  keton-,  or  dibasic  acids  with  three  carbon  atoms 
or  those  acids  with  more  than  three  carbon  atoms  that  easily 
change  to  such  by  decomposition  in  the  body  were  injected  to- 
gether with  the  urea  then  uric  acid  is  formed.     He  found 


COOH 
I 
malonic  acid,        CH^ 

COOH 


COOH 

I 
tartronic  aid,   CHOH 

COOH 


COOH 

I 


COOH 


mesoxahc  acid,     CO         hydracryhc  acid,   CH. 

COOH  CH.OH 


acetyl  formic 
acid, 


COOH 

COOH 

CO 

1 

lactic  acid, 

CHOH 

CH, 

CH, 

1  H.   Wiener.     Ueber  synthetische  Bildung  der   Harnsiiure  im   Tierkorper.     Beitrrige 
z.  cher.i.  Physiol,  u.  Path.,  2,  242  (1902). 


100    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 


CH,OH 


CH, 


/3-oxy-    CHOH 


and  glycerin,  *^HOH       ^^^^  active,      butyric   I  less  active, 


CH,OH 


CH, 


acid 


COOH 
COOH 


CO 


and  a-oxy-bu-        ,2  ^  ■   ■        •  i    i     ■     • 

.  ,  I  and  succinic  acid    i         inactive. 

tync  acid,  CHOH  CH, 

COOH  COOH 

Calling  to  mind  the  synthesis  of  uric  acid  from 
NH  — CHOH 

isodialuric  acid,      CO      CO  and  urea, 

NH  —  CO 

COOH 

and  also  from  malonic  acid,    CHg       and  urea, 

COOH 

we  may  get  a  hint  as  to  how  the  synthesis  may  take  place  in  the 
living  organism. 


NH, 


NH,. 


CH2OH 

COOH 

CH, 

CH, 

1 

COOH 

COOH 

hydracrylic  acid 

malonic  acid 

CH30H 

CH3 

CH.OH 

COOH 

CHOH 
1 

CHOH 

CHOH 

CHOH 

CH2OH 

COOH 

COOH 

COOH 

glycerin 

lactic  acid 

glyceric  acid 

tartronic  acid 

CH3 

COOH 

CO 

CO 

COOH 

COOH 

,  acetyl  formic  acid 

mesoxalic  acid 

The  table  shows  the  substances  found  by  Wiener  most  active, 
and  shows  their  relations  to  one   another.     The   dibasic   acids 


Physiology  101 

containing  a  chain  of  three  carbon  atoms  were  found  to  be  the 
most  active.  That  is  to  say,  from  malonic  acid,  tartronic  acid, 
and  mesoxahc  acid  there  is  obtained  in  the  mine  the  amount  of 
uric  acid  theoretically  required  by  a  combination  of  one  molecule 
of  the  acid  with  two  of  urea.  The  other  active  substances  give 
a  quantity  less  than  that  theoretically  expected,  showing  that 
they  do  not  wholly  change  to  uric  acid. 

While  a  number  of  compounds  can  unite  with  urea  to  give  uric 
acid  in  the  normal  organism,  yet  in  the  isolated  liver  only  tartronic 
acid  and  its  ureide,  dialuric  acid,  are  found  active.  From  this 
we  must  conclude  that  the  other  active  substances  change  first 
to  tartronic  acid,  malonic  and  mesoxalic  acid  completely,  the 
other  active  substances  less  completely.  This,  too,  seems  prob- 
able from  the  chemical  constitution  of  these  compounds.  This 
synthesis  of  uric  acid  from  urea  and  tartronic  acid  is  represented 
by  the  following  reactions,  and  can  be  carried  on  outside  the 
living  body: 


2H,0 


NH^ 

COOH 

NH  — CO 

CO 

+ 

CHOH     = 

CO       CHOH       4 

NHj 

COOH 

NH  — CO 

urea 

tartronic  acid 

dialuric  acid 

NH  — CO 

CO       CHOH 

1           1 
NH— CO 

+ 

NH,\ 

"  ;co 

NH,/ 

NH  — CO 

=       CO      C— NH 

1           II 
NH— C  — NH 

dialuric  acid 

uric  acid 

CO    +    2H,0 


The  fact  that  Kowalewski  and  Salaskin^  synthesized  uric  acid 
from  ammonium  lactate  by  passing  the  latter  together  with  geese 
blood  through  extirpated  geese  livers,  taken  together  with  the 
fact  that  ammonia  and  lactic  acid  are  found  in  geese  urine  after 
liver  extirpation,  indicates  that  the  oxidation  of  lactic  acid  to 
tartronic  acid  is  also  a  function  of  the  liver.  The  dead  liver, 
however,  at  least  of  mammals,  as  Wiener's  work  showed,  is  not 
able  to  carry  on  this  process.  We  see,  too,  that  the  change  from 
ammonia  to  urea  in  the  synthetic  formation  of  uric  acid  must 
take  place  in  the  liver,  since  it  does  not  take  place  in  geese  with 
extirpated  livers,  and  since  the  synthesis  of  uric  acid  from  am- 
monia does  take  place  in  the  isolated  liver. 

1  K.  Kowalewski  und  S.  Salaskin.  Ueber  die  Bildung  von  Harnsaure  in  der  Leber  der 
Vogel.     Zeitschr.  fur  physiol.  Chem.,  33,  210  (1901). 


102    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

It  may  be  of  interest  to  state  at  this  point  that  as  late  as 
1893  Garrod  stated  ^  that  uric  acid  is  probably  synthesized  in 
the  kidneys  of  birds  from  glycocoll  and  urea.  He  stated  that 
he  did  not  find  uric  acid  in  the  blood,  and  that  uric  acid  can  be 
synthesized  from  glycocoll  and  urea  "  extra  corpus,"  as  proof  of 
this  theory. 

It  is  not  known  whether  ammonia  Avith  tartronic  acid  can  be 
synthesized  to  uric  acid  by  the  action  of  fresh  chopped  up  bird 
or  mammal  livers,  that  is,  if  the  first  part  of  the  synthesis,  the 
change  from  ammonia  to  urea,  can  take  place  in  this  way.  The 
question  also  comes  up  if  uric  acid  can  be  synthesized  by  passing 
through  extirpated  geese  livers  blood  containing  ammonia  or 
urea  together  with  malonic  acid,  hydracrylic  acid,  or  the  other 
bodies  found  to  act  as  sources  of  the  non-nitrogenous  part  of 
uric  acid.  Further,  it  would  be  of  interest  to  know  if  these 
active  bodies  pass  unchanged  through  the  organism  of  geese 
with  extirpated  liver  or  to  what  they  decompose,  and  to  know  if 
cut-up  bird  livers  can  bring  about  the  change  from  lactic  to 
tartronic  acid  in  the  synthesis  of  uric  acid.  We  hope  to  make 
an  experimental  study  of  these  questions  and  others  suggested 
by  these. 

Wiener  ^  found  that  carbohydrates  and  fats,  or,  more  exactly, 
grape  sugar  and  olive  oil,  as  well  as  proteid,  could  serve  as  sources 
of  uric  acid  in  birds.  In  the  case  of  fats,  this  may  be  accounted 
for  by  the  fact  that  the  glycerin  is  a  source  for  the  non-nitroge- 
nous part  of  the  uric  acid.  The  action  of  the  carbohydrates  is 
•  undoubtedly  due  to  a  similar  cause,  as  the  structural  formulse  of 
the  sugars  would  indicate. 

Uric  Acid  Formed  in  Birds  by  Oxidation 

Mach  ^  called  attention  to  the  fact  that  even  after  liver  extir- 
pation there  is  a  small  amount  of  uric  acid  still  excreted  by  birds. 
He  thought  that  this  might  be  formed  by  oxidation  of  purin 
bodies  from  nucleo-proteids,  for  he  found  that  administration 
of  hypoxanthin  increases  the  excretion  of  uric  acid  in  birds  as  in 

*  A.  Garrod.  On  the  Presence  of  Uric  Acid  in  the  Blood  of  Birds,  and  Its  Bearing  upon 
the  Formation  of  Uric  Acid  in  the  Animal  Body.     Proc.  Roy.  Soc,  53,  178  (1893). 

2  Wiener.  Ueber  synthetische  Bildung  der  Harnsaure  im  Tierkorper.  Beitrage  z . 
chem.   Physiol,   u.   Path.,   2,   42   (1902). 

3  W.  V.  Mach.  Ueber  die  Umwandlung  von  Hypoxanthin  in  Harnsaure  im  Organismus 
der  Vogel.     Arch.  f.  exp.  Path.  u.  Pharmak.,  23,  148  (1887). 


Physiology  103 

mammals.  In  a  later  article/  Mach  showed  that  the  adminis- 
tration of  hypoxanthin  increases  the  excretion  of  uric  acid  even 
in  hens  with  extirpated  liver,  so  that  this  uric  acid  is  due  to  an 
oxidation  process  and  not,  as  the  bulk  of  the  uric  acid  excreted  by 
birds,  to  a  synthesis.  According  to  more  recent  experiments  of 
Milroy,^  the  administration  of  nucleic  acid,  or  hypoxanthin,  to 
birds  with  extirpated  liver,  increases  the  mono-  and  di-amino 
nitrogen  of  the  urine,  but  not  the  uric  acid. 

The  general  question  of  a  formation  of  uric  acid  by  oxidation 
of  purin  bodies  will  be  discussed  at  length  in  a  later  section. 

Wiener  ^  maintains,  in  common  with  most  physiologists,  that 
more  uric  acid  is  formed  in  mammals  than  is  excreted,  and  that  a 
part  is  decomposed  and  excreted  as  urea;  and  we  know  that  in 
birds  a  large  part  of  the  urea  formed  is  changed  to  uric  acid. 
Hence,  Kowalewski  and  Salaskin  *  have  expressed  the  view  that 
in  both  birds  and  mammals  all  the  uric  acid  and  urea  formed  is 
not  excreted  as  such,  but  that  some  of  each  changes  to  the  other. 

We  have  seen,  then,  that  in  birds  the  end  product  of  nitroge- 
nous metabolism  is  chiefly  uric  acid,  that  the  larger  part  of  this 
is  formed  by  synthesis,  and  that  a  small  part  comes  from  purin 
bodies  by  oxidation.  The  synthetic  uric  acid  is  made  up  of  two 
parts,  the  nitrogenous  and  the  non-nitrogenous.  The  nitrogenous 
portion  comes  from  the  proteid  of  the  food  and  of  the  body.  The 
non-nitrogenous  part  may  come  from  the  proteid,  fat  and  carbo- 
hydrates of  the  body  or  of  the  food.  The  source  of  the  'uric  acid 
formed  by  oxidation  will  be  discussed  in  the  section  on  uric  acid 
in  mammals. 

Uric  Acid  in  Mammals 

Formation  of  Uric  Acid  in  the  Body 

The  question  of  the  source  of  the  uric  acid  excreted  by  mammals 
is  one  that  has  given  rise  to  as  much  discussion  probably  as  any 
question  in  the  field  of  physiological  chemistry.  The  early 
physiologists    looked    upon  uric  acid    as  an  antecedent  of   urea 

1  W.  V.  Mach.  Ueber  die  Bildung  der  Harusaure  aus  Hypoxanthin.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  24,  389  (1888). 

2T.  Milroy.     The  Formation  of  Uric  Acid  in  Birds.     .Tour,  of  Physiol.,  30,  47  (1903). 

3  H.  Wiener.  Ueber  Zersetzung  und  Bildung  der  Harns.aure  im  Tierkorper  Verhandl. 
des  17t  Kongr.  fiir  innere  Medizin,  622  (1899),  and  Arch,  fiir  exp.  Path.  u.  Pharmak.,  42,  375 
(1899). 

*  K.  Kowalewsky  und  S.  Salaskin.  Ueber  den  Ammoniak  und  Milchs.auregehalt  im 
Blute  und  iiber  die  Stickstoffvertheilung  im  Harne  von  Gansen  unter  verschiedenen  Ver- 
haltnissen.     Zeitschr.  fiir  physiol.  Chem.,  35,  552  (1902). 


104    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

in  that  series  of  proteid  oxidation  products,  the  final  product 
of  which  is  urea.  An  excretion  of  a  large  amount  of  uric  acid 
they  looked  upon  as  an  evidence  of  deficient  oxidation. 

It  will  be  shown  that  this  view  of  uric  acid  as  a  product  of 
partial  oxidation  of  proteid  is  an  erroneous  one.  Since,  however, 
some  recent  writers  maintain  that  proteid  can  serve  as  a  source 
for  uric  acid,  not,  however,  in  the  manner  in  which  it  was  be- 
lieved to  do  so  by  the  old  writers,  but  after  first  forming  urea  as 
in  birds,  the  question  of  a  formation  of  uric  acid  from  urea  will  be 
reserved  for  a  later  section. 

We  shall  first  discuss  what  are  probably  the  most  important 
sources  of  uric  acid  in  the  mammal,  that  is,  the  purin  bodies  and 
the  nucleins  and  nucleoproteids  which  on  decomposition  give 
purin  bodies. 

FROM  NUCLEO-PROTEIDS,  NUCLEINS,  AND  PURIN  BODIES 

On  account  of  the  great  importance  of  the  nucleoproteids  as  a 
source  of  uric  acid  in  mammals,  a  short  sketch  will  be  given  of 
their  chemistry  and  their  relation  to  the  other  proteids. 

Chemistry  and  Occurrence  of  the  Nucleoproteids  and  Purins 

Cohnheim  ^  gives  the  following  division  of  the  protein  bodies : 

1.  Simple  Proteids. 
(1.)  Albumins. 

Seralbumin,   ovalbumin,  lactalbumin. 
(2.)  Globulins. 

Serum   globulin,  egg  globulin,  lactoglobulin,  cellglobu- 
lin,  plant  globuhns. 
(3.)  Coagulating  Proteids. 

Fibrinogen,  myosin,  myogen,  gluten. 
(4.)  Nucleo-albumins. 

Casein,    vitellin,    phytovitellin,   nucleo-albumin   of    the 
cell  protoplasm,  mucilaginous  nucleo-albumins. 
(5.)  Histon. 
(6.)   Protamin. 

2.  Derived  Albumins. 

(1.)  Acid  Albumin  and  Alkali  Albumin. 
(2.)  Albmnoses  and  Peptones. 

3.  Proteids. 

(1.)  Nucleoproteids. 

1  O.  Cohnheim.     Chemie  der  Eiweisskorper,  pp.  82  und  S3.     Braunschweig,  1900. 


Physiology  105 

Compounds  of    nucleic  acid  with  (a)  histon,  (6)    prot- 
amin,  (c)  other  proteids. 
(2.)  Hcemoglobin. 

Compounds  of  hsematin  with  histon. 
(3.)  Glycoproteids. 

Compounds  of  proteid  with  glucosamin  and  other  carbo- 
hydrates. 
Mucins,  mucoids,  helicoproteid. 
4.  Albuminoids. 
(1.)  Collagen. 
(2.)  Keratin. 
(3.)  Elastin. 

(4.)  Spongin,  fibroin,  etc. 
(5.)  Amyloid. 
(6.)  Albumoid. 

(7.)  Coloring  substances  from  proteid. 
This  table  shows  the  relation  of  the  nucleoproteids  to  the 
other  protein  bodies.  The  proteids  are  compounds  of  simple 
proteids  with  non-proteid  bodies.  They  are  thus  in  a  way  analo- 
gous to  glucosides,  which  are  compounds  of  glucose  with  other 
bodies. 

The  nucleoproteids  were  discovered  by  Miescher  ^  and  Plocz,^ 
but  their  physical  and  chemical  properties  have  only  very  re- 
cently been  understood.  On  digestion  with  pepsin  hydrochloric 
acid,  or  on  boiling  with  hydrochloric  acid,  the  nucleoproteids 
split  into  a  simple  proteid,  usually  either  histon  ^  or  protamin  ^ 
and  a  body  containing  a  larger  percentage  of  phosphorus,  —  a 
nuclein.  The  nuclein,  too,  is  a  compound  proteid,  and  on  further 
treatment  with  acid  decomposes  into  a  simple  proteid  and  nu- 

1 F.  Miescher.  Chemische  Zusammensetzung  der  Eiterzelle.  Hoppe-Seyler's  Med.- 
Chem.  Untersuch.,  p.  44  (1871). 

2  P.  Plocz.  Kerne  der  Vogel-  und  Schlangenblutkorperschen.  Hoppe-Seyler's  Med.- 
Chem.  Untersuch.,  p.  461  (1871). 

3  J.  Bang.     Studien  uber  Histon.     Zeitschr.  fur  physiol.  Chem.,  27,  463  (1899). 
*  F.  Miescher.     Verhandl.  der  naturforsch.  Ges  zu  Basel,  6,  138  (1874). 

Ibid.     Lachsmilch.     Schmiedeberg's  Arch,  fiir  exp.  Path.  u.  Phar.,  37,  100  (1896). 

A.  Kossel.  Ueber  die  basischen  Stoffe  des  Zellkerns.  Zeitschr.  fiir  physiol.  Chem., 
22,  176  (1896). 

Ibid.  Ueber  die  Konstitution  der  einfachsten  Eiweisstoffe.  Zeitschr.  fiir  physiol. 
Chem.,  25,  165  (1898). 

A.  Mathews.  Zur  Chemie  der  ^permatozoen.  Zeitschr.  fur  physiol.  Chem.,  23,  399 
(1897). 

D.  Kurajeff.  Ueber  das  Protamin  aus  dem  Spermatozoen  der  Makrele.  Zeitschr.  fur 
physiol.  Chem.,  26,  524  (1898). 

N.  Morkowin.  Ein  Beitrag  zur  Kenntniss  der  Protamine.  Zeitschr.  fiir  physiol. 
Chem.,  28,  313  (1899). 


106    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

cleic  acid/  —  a  body  containing  still  more  phosphorus  than  the 
nuclein.  On  boiling  nucleic  acid  for  a  short  time  with  acid, 
certain  purin  bases  spht  off/  also  a  carbohydrate/  usually  a 
pentose,  sometimes  also  a  hexose,  phosphoric  acid,  ammonia/ 
formic  acid/  and  probably  other  bodies. 

The  following  sketch  shows  graphically  how  the  nucleoproteids 
decompose  on  treatment  with  acid. 

Nucleoproteid 


/ 


/ 


Simple  proteid  Nuclein 

usually  either  ,  . 

protamin  or  histon  /      \ 


Simple  proteid 

usually  either 

protamin  or  histon 


Purin  Bases 
guanin 
adenin 
xanthin 
hypoxanthin 


Nucleic  acid 


carbohydrate 


phosphoric 
acid 


ammonia, 

formic  acid 

and  so  forth 


1  R.  Altmann.  Ueber  Nucleinsaure.  Arch.  f.  Anat.  u.  Physiol.  Physiol.  Abth.  1889, 
p.  524. 

A.  Kossel.  Ueber  die  Nucleinsaure.  Arch.  f.  Anat.  u.  Physiol.,  1893,  p.  157,  and 
numerous  papers  by  Kossel  and  his  pupils  and  Schmiederberg,  especially  in  the  Zeitschr. 
fur  physiol.  Chem.  and  the  Arch.  f.  exp.  Path.  u.  Pharmak. 

2  Kossel  und  Neumann.  Ueber  das  Thymin,  ein  Spaltungsprodukt  der  Nucleinsaure. 
Ber.  d.  Dtsch.  chem.  Gesell.,  26,  2753  (1893). 

Kossel  und  Steudel.  Ueber  Nucleinsaure  und  Thyminsaure.  Zeitschr.  fiir  physiol. 
Chem.,  22,  74  (1896). 

3  A.  Kossel.  Ueber  die  Chemische  Zusammensetzung  der  Zelle.  Arch.  f.  Anat.  u. 
Physiol.,  1891,  181. 

Ibid.     Ueber  die  Nucleinsaure.     Arch.  f.  Anat.  u.  Physiol.,  1893,  157. 

O.  Hammarsten.  Zur  Kenntniss  der  Nucleoproteide.  Zeitschr.  fiir  physiol.  Chem., 
19,  19  (1893). 

*  Kossel  und  Neumann.  Darstellung  und  Spaltungsprodukte  der  Nucleinsaure.  Ber. 
der  Dtsch.  chem.  Gesell.,  27,  2215  (1894). 

Bang  und  Neumann.  Zur  Kenntniss  der  Nuclein substanzen.  Arch.  f.  Anat.  u.  Physiol., 
1898,  374. 


Physiology  107 

It  must  be  understood  that  this  sketch  of  the  chemistry  of  the 
nucleoproteids  is  not  intended  to  be  thorough.  It  is  given  simply 
in  order  to  show  how  the  purin  bases  are  obtained  as  decomposi- 
tion products  of  the  nucleoproteids  by  hydrolytic  sphtting 
"  extra  corpus/'  and  therefore  how  they  might  be  expected  possi- 
bly to  be  obtained  as  decomposition  products  in  the  living  organ- 
ism. According  to  Kossel/  nucleic  acid  can  be  split  into  purin 
bases  and  another  definite  compound,  thymic  acid,  free  from  the 
purin  bases.  The  chemistry  of  the  nucleoproteids  is  at  present 
engaging  the  attention  of  numerous  workers,  for  there  is  much 
to  learn  about  the  subject. 

In  the  organism,  nucleoproteid  alone,  not  nuclein  or  nucleic 
acid,  is  found.  Nucleoproteid  is  the  only  protein  substance 
giving  purin  bodies  as  decomposition  products.  The  purin 
bodies  thus  found  are  adenin,  guanin,  xanthin,  and  hypoxan- 
thin.  In  some  nucleoproteids  all  four  bases  are  found,  and  in 
some  others  only  one  or  two  of  them.  The  fractional  amounts 
of  proteid,  purin  bases,  carbohydrates,  and  so  forth  in  the  nucleo- 
proteids have  not  been  accurately  studied. 

The  nucleoproteids  occur  only  as  components  of  the  cells  of 
the  organism,  and  not  in  solution  in  the  animal  jviices,  although 
they  are  sometimes  found  in  blood  serum  and  other  fluids  after 
cell  destruction.  They  are  the  chief  constituents  of  the  cell 
nuclei,  and  therefore  foimd  in  large  amounts  in  organs  rich  in 
cells,  and  are  probably  not  abundant  in  the  cell  protoplasm  out- 
side of  the  nucleus.  Lilienfeld  ^  has  found  the  dry  substance 
of  the  thymus  leucocytes  to  consist  of  77  per  cent  nucleoproteid 
(nucleo-histon) ,  and  Miescher  and  Schmiedeberg  ^  have  found 
the  heads  of  the  ripe  spermatozoa  of  fish  to  consist  of  96  per  cent 
of   nucleoproteids. 

The  work  of  Burian  on  the  mode  of  combination  of  the  purin 
bases  in  nucleic  acid  is  of  interest.  It  will  be  remembered  *  that 
this  author  showed  that  the  purin  bodies  in  which  the  hydrogen 
atom  at  position   (7)  is  not  substituted  can  be  diazotized.     He 

1  A.  Kossel  und  H.  Steudel.  Ueber  Nucleinsaure  und  Thyminsaure.  Zeitschr.  fiir 
physiol.  Chem.,  22,  74  (1896). 

2  L.  Lilienfeld.  Zur  Chemie  der  Leucocyten.  Zeitschr.  fiir  physiol.  Chem.,  IS,  473 
(1894). 

3  F.  Miescher  und  Schmiedeberg.  Physiologische-chemische  Untersuchungen  ueber 
die  Lachsmilch.     Schmiedeberg's  Arcliiv.,  fiir  exp.  Path.  u.  Pharmak.  37,  100  (1896). 

*  See  page  8;  also  R.  Burian.  Diazoverbindungen  der  Imidazole  und  der  Purinsub- 
stanzen.     Ber.  der  Dtsch.  chem.  Gesell.,  37,  696  (1904). 


108    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

then  studied  the  nucleic  acids,  and  found  that  in  spite  of  their 
high  content  of  purin  base,  they  cannot  be  diazotized.^  This  is 
not  due  to  something  which  prevents  the  reaction,  for  guanin 
will  react  with  diazo-bodies  in  the  presence  of  nucleic  acid. 
Burian  concludes,  therefore,  that  either  the  base  is  not  quite 
ready  formed  in  the  nucleic  acid,  or  that  it  is  combined  with  the 
rest  of  the  nucleic  acid  molecule  at  position  (7).  On  account  of 
the  ease  with  which  the  bases  are  split  from  the  acid,  he  thinks 
that  the  latter  condition  is  probably  true.  According  to  this 
author,  the  base  is  probably  combined  directly  with  the  P  rather 
than  with  O,  or  C,  for,  like  certain  phosphoric  acid  amides,  for 
example,  dianilidophosphoric  acid, 

CeH,NH-P  =  0, 

oh/ 

and  anilidophenylphosphinic  acid, 

CeHgNH  — P=0 
OH  / 

they  easily  decompose  with  boiling  water  or  HCl,  but  are  only 
slowly  dissolved  by  boiling  NaOH.  According  to  Steudel,^ 
Burian 's  conclusions  were  not  warranted  by  his  results,  but 
Burian  ^  has  answered  Steudel's  objections  very  satisfactorily. 

Considerable  work  has  been  done  recently  on  the  occurrence 
of  the  individual  purin  bodies  in  the  nucleoproteids  of  the  different 
organs.  According  to  Kossel,'*  thymus  nucleic  acid  contains 
chiefly  adenin.  SteudeP  found  guanin,  adenin,  xanthin,  and 
hypoxanthin.  Jones  '^  found  xanthin  and  a  small  quantity  of  hypo- 

'  R.  Burian.  Zur  Kenntnis  der  Bindung  der  Purinbasen  im  Nukleinsauremolekule. 
Ber.  d.  Dtsch.  chem  Gesell.,  37,  708  (1904). 

2  H.  Steudel.  Zur  Kenntniss  der  Thyrnusnucleinsauren.  Zeitschr.  fiir  physiol.  Chem., 
42,   165  (1904). 

3  R.  Burian.  Zur  Frage  der  Bindung  der  Purinbasen  im  Nukleinsauremolekule. 
Zeitschr.  fiir  physiol.  Chem.,  42,  297  (1904). 

^  A.  Kossel.  Ueber  einiger  Bestandtheile  thierischen  Zellen.  Arch,  fiir  Anat.  u. 
Physiol.  (1894),  551. 

5  H.  Steudel.  Zur  Kenntniss  der  Thymusnukleinsauren.  Zeitschr.  fiir  physiol.  Chem., 
42.  165  (1904),  und  43,  402  (1905). 

"  W.  Jones.  Ueber  die  Selbstverdauung  von  Nukleoproteid.  Zeitschr.  fur  physiol. 
Chem.,  42,   35   (1904). 


Physiology  109 

xanthin  in  thymus  which  had  undergone  autolysis.  Neumann/ 
Bang,^  Huiskamp,^  and  Kostytschew  ^  have  found  more  than 
one  nucleoproteid  in  thymus  glands.  Bang''  found  guanin, 
and  Bang  and  Raaschou  ^  guanin  only  in  the  pancreas,  but 
Levene  ^  has  found  both  guanin  and  adenin  in  fresh  spleen.  In 
spleen  which  has  undergone  self-digestion,  Levene  found  hypo- 
xanthin,  xanthin,  and  some  guanin,  but  no  adenin.  Schenk  ^ 
could  find  only  guanin  and  hypoxanthin  in  spleen  which  has 
undergone  autolysis.  Spleen  nuclein  contains  guanin  according 
to  Jones,^  adenin  and  guanin  according  to  Levene.^"  In  spleen 
which  had  undergone  self -digestion  Levene  "  found  chiefly  hypo- 
xanthin. In  fresh  liver  the  nucleoproteid  contains  adenin,  guanin, 
hypoxanthin,  according  to  Levene/^  and  xanthin  also  according 
to  Wohlegemuth.^^  Levene  ^^  found  adenin,  hypoxanthin,  and 
xanthin  in  liver  which  had  undergone  autolytic  digestion.  Biondi  ^^ 
did  not  find  any  purin  bases  in  calves'  liver  which  had  undergone 
self-digestion.     Kossel  ^*    found    xanthin,   hypoxanthin,   adenin, 

1  A.  Neumann.  Arch.  f.  Anat.  u.  Physiol.,  344  (1S98),  und  Verfahren  zur  Darstellung 
der  Nucleinsauren  a  und  h  und  der  Nucleothyminsaure.  Arch.  f.  Anat.  u.  Physiol.,  552 
(1899). 

- 1.  Bang.  Benierkungen  iiber  das  N ucleohiston.  Zeitsnhr.  fiir  physiol.  Chem.,  30,  509 
(1900). 

Chemische  Untersuchungen  der  lymphatischen  Organe.  Hofmeister's  Beitrage,  4, 
115  (1903). 

^W.  Hmskamp.  Ueber  die  Eiweisskorper  der  Thymusdruse.  Zeitschr.  fiir  physiol. 
Chem.,  32,   145  (1901). 

Beitrage  zur  Kenntnis  der  Thymusnukleohiston.  Zeitschr.  fiir  physiol.  Chem.,  39,  55 
(1903). 

*■  S.  Kostytschew.  Ueber  Thymonukleinsaure.  Zeitschr.  fiir  physiol.  Chem.,  39,  545 
(1903). 

■''  I.  Bang.  Die  Gu.anylsaure  der  Pancreasdriise  und  deren  Spaltungsprodukte.  Zeitschr. 
fiir  physiol.  Chem.,  26,  133  (1898). 

6 1.  Bang  und  C.  Raaschou.  Darstellung  der  Guanylsaure  Hofmeister's  Beitrage,  4, 
175  (1903). 

^  P.  Levene.  Darstellung  und  Analyse  einiger  Nucle'insaure.  Zeitschr.  fiir  physiol. 
Chem.,  37,  402  (1903). 

The  Autolysis  of  Animal  Organs.  II.  Hydrolysis  of  li'resh  and  Self-digested  Glands. 
Am.  Journ.  of  Physiol.,  12,  276  (1904). 

s  M.  Schenk.  Die  bei  der  Selbstverdauung  des  Pankreas  auftretende  Nukleinbasen. 
Zeitschr.  fiir  physiol.  Chem.,  43,  406  (1905). 

8  VV.  Jones.  Ueber  die  Selbstverdauung  von  Nukleoproteid.  Zeitschr.  fiir  physiol. 
Chem.,  42,  35  (1904). 

1"  P.  Levene.  Darstellung  und  Analyse  einiger  Nucleinsaure.  Zeitschr.  fiir  physiol. 
Chem.,  32,  541  (1901). 

"  Ihid.  The  Autolysis  of  Animal  Organs.  II.  Hydrolysis  of  Fresh  and  Self-digested 
Glands.     Am.  Journ.  of  Physiol.,  12,  816  (1904). 

12  J.  Wohlegemuth.  Ueber  das  Nukleoproteid  der  Leber.  Zeitschr.  fiir  physiol.  Chem., 
42,  519  (1904). 

'3  C.  Biondi.  Beitrage  zur  Lehre  der  fermentativen  Prozesse  in  den  Organen.  Vir- 
chow's  Archiv,  144,  373,  1896. 

"A.  Kossel.     Ueber  Nukleinsaure.     Arch.  f.  Anat.  u.  Physiol.  (1S93),  157. 


110    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

and  guanin  in  yeast  nucleic  acid.  Kutscher  ^  found  guanin  and 
adenin  in  yeast  which  had  undergone  autolysis,  and  Schittenhelm 
and  Schroter  ^  found  that  xanthin  and  hypoxanthin  are  formed 
when  the  yeast  nucleic  acid  is  decomposed  by  bacteria.  Leu- 
cocytes contain  adenin  and  hypoxanthin.^  In  fresh  spermatozoa 
are  found  adenin  and  guanin;  ^  in  self-digested  spermatozoa, 
hypoxanthin  and  xanthin.*  The  red  blood  corpuscles  contain 
only  adenin.^  In  the  fresh  suprarenal  gland  there  is  guanin  and 
adenin;  "^  in  that  which  has  undergone  self -digestion  there  is 
found  xanthin,  hypoxanthin,  and  1-methylxanthin.'^  In  the 
nucleic  acid  of  the  brain  Levene  ^  found  adenin  and  guanin.  We 
shall  see  later  in  the  discussion  of  the  metabolism  of  the  individual 
purin  bodies  that  these  organs  contain  enzymes  capable  of  chang- 
ing the  amino  puri«is  to  oxypurins.  This  explains  why  it  is  that 
the  same  purin  bases  are  not  always  found  in  the  self-digested 
organs  as  are  found  in  the  fresh  organs. 

Very  little  nucleoproteid  is  found  in  ordinary  meat,®  but  it 
has  long  been  known  that  free  hypoxanthin  does  occur.  Strecker  ^ 
found  .022  per  cent  hypoxanthin,  Stadeler  ^^  .016  per  cent,  and 
Neubauer  "  .016  to  .027  per  cent  in  beef  muscle,  and  Scherer  '^ 

1  F.  Kutscher.  Chemische  Untersuchungen  iiber  die  Selbstgahrung  der  Hefe.  Zeitschr. 
fiir  physiol.  Chem.,  32,  59  (1901). 

2  A.  Schittenhelm  und  F.  Schroter.  Ueber  die  Spaltung  der  Hefennukleinsaure  durch 
Bakterien,  IV.     Mittheilung.     Zeitschr.  fur  physiol.  Chem.,  41,  284  (1904). 

3  O.  Schmiedeberg.  L'eber  die  Nucleinsaure  aus  der  Lachsmilch.  Arch.  f.  exp.  Path. 
u.  Pharmak.,  43,  57  (1S99). 

P.  Levene.  Darstellung  und  Analyse  einiger  Nucleinsaure.  Zeitschr.  fiir  physiol.  Chem., 
39,  479  (1903). 

*  J.  Mochizuki  und  Y.  Kotak.  Ueber  die  Aiitolyse  der  Stierhoden.  Zeitschr.  fiir  physiol. 
Chem.,  43,   165  (1904). 

5  Y.  Inoko.  Einige  Bemerkungen  iiber  phosphorhaltige  Blutfarbstoffe.  Zeitschr.  fiir 
physiol.  Chem.,  18,  57  (1894). 

L.  Lilienfeld.     Zur  Chemie  der  Leucocyten.    Zeitschr.  fiir  physiol.  Chem.,  18,  473  (1894). 

"  Whipple  and  Whipple.  The  nucleoproteid  of  the  suprarenal  gland.  Am.  Journ.  of 
Physiol.,  7,  423  (1902). 

''J.  Okerblom.  Die  Xanthinkorper  der  Nebennieren.  Zeitschr.  fiir  physiol.  Chem., 
28,  60  (1899). 

8  C.  Pehelharing.  Ueber  das  Vorhandsein  eines  Nukleoproteids  in  Muskeln.  Zeitschr. 
fur  physiol.  Chem.,  22,  245  (1896). 

9  A.  Strecker.  Ueber  das  Sarkin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  108,  129 
(1858). 

1°  Stadeler.  Ueber  eine  leichte  Darstellungsweise  des  Xanthins  und  der  sich  ausschlies- 
senden  Stoffe  aus  thierischen  Organen.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  116,  105 
(1860). 

"  C.  Neubauer.  Ueber  die  quantitative  Bestimmung  des  Sarkin  und  Xanthins  in 
Muskelfleisch.     Frezenius'  Zeitschr.  fiir  analyt.  Chem.,  6,  33  (1867). 

^2  Scherer.  LTeber  Hypoxanthin,  Xanthin,  und  Guanin,  im  Thierkorper  und  den  Pieich- 
thum  der  Pancreasdruse  an  Leucin.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  112,  257 
(1859). 


Physiologij  111 

found  .014  per  cent  in  horse  flesh.  These  authors  extracted  the 
meat  with  cold  water  and  anah^zed  the  extract.  This  method 
does  not  give  the  hypoxanthin  in  the  inosinic  acid  which  Haiser  ^ 
found  in  muscle  and  which  he  showed  contains  hypoxaiithin. 
KosseP  and  Monari,^  by  methods  whose  accuracy  has  been 
questioned,  found  larger  amounts  of  hypoxanthin  and  also  some 
xanthin  in  muscle.  According  to  ]\licko/  meat  extract  contains 
chiefly  hypoxanthin  with  some  xanthin  and  a  trace  of  adenin,  but 
no  guanin.  Burian  and  Schur;''  by  a  method  which  is  probably 
more  accurate  than  the  methods  of  their  predecessors,  found  .045 
per  cent  free  purin  bases  and  .015  per  cent  combined  purin 
bases. 

Concerning  the  presence  of  purin  bases  in  fish,  I  am  aware  of 
the  work  only  of  Schmidt-Nielson^  and  Isaac,^  who  found  chiefly 
guanin,  with  smaller  amounts  of  adenin  and  hypoxanthin,  and 
traces  of  xanthin  in  pickled  herring  brine. 

Kossel^  and  Petren  ^  analyzed  milk  for  purin  bodies,  but  could 
find  none.  Schmidt-Miilheim  ^°  stated  that  he  isolated  hypo- 
xanthin crystals  from  milk,  but  he  did  not  say  to  what  extent 
they  were  present.  The  work  of  Burian  and  Schur"  shows  only 
the  insignificant  amount  of  .004  to  .006  grain  purin  bodies 
per  liter  in  milk. 

The  nuclein  of  egg  yolk  is  only  a  pseudonuclein,  and  egg  con- 
tains no  purin  bodies,  according  to  Kossel,^  Petren,^  and  Burian 
and  Schur.-' 

1 F.  Haiser.  Zur  Kenntnis  der  Inosinsaure.  Monatshefte  fiir  Chem.,  16,  190 
(.1895). 

2  A.  Kossel.  Zur  Chemie  des  Zellkernes.  Zeitschr.  fiir  physiol.  Chem.,  7,  7 
(1882). 

Ueber  Guanin.     Zeitschr.  fiir  physiol.  Chem.,  8,  404  (1884). 

^Monari.     Arch,  italiennes  de  Biologie,  13,  1   (1890). 

*  K.  Micko.  Untersuchungen  von  Fleisch,  Hefen-  und  anderen  Extrakter  auf  Xan- 
thinkorper.     Zeitschr.,  Unters.  Nahr-  und  Genussm.,  6,  781  (1903). 

5  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purimkorper  in  menschlichen  Stoff- 
wechsel.     Pfliiger's  xVrch.,  80,  241  (1900). 

8  Schrcidt-Nielson.  Zur  Kenntniss  der  Autolyse  des  Fischfieisches.  Hofmeister's  Bei- 
triige,  3,  266  (1903). 

^  S.  Isaac.     Die  Purinbasen  der  Heringslake.     Hofmeister's  Beitrage,  5,  500  (1904). 

8  Kossel.  Medicinisch-chemisch.  Untersuchungen  von  Hoffe-Seyler,  502.  Tiibingen 
(1871). 

Ibid.  Weitere  Beitrage  zur  Chemie  des  Zellkerns.  Zeitschr.  fiir  physiol.  Chem  10, 
248  (1886). 

**  K.  Petr^n.  Nachtrag  zur  Jfitterlung  iiber  das  Vorkommen  der  Xanthinbasen  in  den 
Faces.     Skandinav.  Archiv  f.  Physiol.,  9,  412  (1899). 

1"  Schmidt-Miilheim.  Leber  Stickstoffhaltiger  Korper  in  der  Kuhmilch.  Pfluger's 
Archiv,  30,  379  (1883). 


112    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Vegetables  do  not,  in  general,  contain  purin  bodies,  but  HalH 
has  found  purin  bodies  in  peas  and  beans,  and  Salomon,^  Reinke 
and  Rodewald,^  Bugarsky/  Schultz  and  Bosshard,^  Salkowski,** 
Kossel,'^  Kossel  and  Neumann,*  Micko,^  v.  Lippmann/^  Shorey," 
and  Bressler^^  have  found  these  bodies  in  small  quantities  in 
certain  plants,  especially  in  very  young  leguminous  plants. 

The  Physiologiccd  Relation  between  the  Nucleoproteids,  Nticleins, 
Nucleic  Acid,  and  Purin  Bases,  and  the  Formation  of  Uric  Acid 
in  the  Mammal  Organism. 

HisTORicAi; :  The  Source  of  Uric  Acid.  —  On  account  of  the 
fact  that  uric  acid  is  easily  oxidized  to  urea,  and  also  that  if  uric 
acid  is  eaten  it  is  excreted  as  urea  by  rabbits,  according  to  Wohler 
and  Frerichs,^^  uric  acid  was  looked  upon  as  an  antecedent  of 
urea  in  the  destructive  metabolism  of  proteid.  Its  presence  in 
the  urine  of  mammals  was  thought  to  be  due  to  incomplete 
oxidation  processes.  This  is  the  view  expressed  by  Liebig^*  and 
Lehmann^^  in  their  textbooks  two  generations  ago.  It  was  the 
view  generally  held  until  within  about  twenty  years.  Although 
historically  first,  we  shall  leave  the  account  of  the  development 
of  this  idea  until  after  treating  of  the  physiological  relations 

II.  Hall.     The  Purin  Bodies  of  Foodstuffs.     Manchester,  Eng.  (1902). 

2  G.  Salomon.     Verhandlungen  der  physiol.     Gesellschaft  in  Berlin,  1880-81,  p.  14. 

3  Reinke  und  Rodewald.  Untersuchungen  aus  dem  botanischen  Laboratorium  in 
Gottingen,  2,  147. 

*  A.  Bugarsky.  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxanthin. 
Zeitschr.  fiir  physiol.  Chem.,  8,  395  (1884). 

5  E.  Schultz  und  E.  Bosshard.  Zur  Kenntniss  des  Vorkommens  von  Allantoin,  Aspari- 
gin,  Hypoxanthin,  und  Guanin  in  den  Pflanzen.  Zeitschr.  fiir  physiol.  Chem.,  9,  420 
(188.5). 

s  E.  Salkowski.  Ueber  Zuckerbildung  und  andere  Fermentationen  in  der  Hefe.  Zeitschr. 
fur  physiol.  Chem.,  13,  527  (1889). 

7  A.  Kossel.     Arch.  Physiol.,  157  (1893). 

8  A.  Kossel  und  A.  Neumann.  Darstellung  und  Spaltungsprodukte  der  Nucleinsaure 
(Adenylsaure).     Ber.  der  Dtsch.  chem.  Gesell.,  27,  2215  (1894). 

"  Micko.  Untersuchungen  von  Fleisch-  Hefen-  und  anderen  Extrakten  auf  Xanthin- 
korper.     Zeitschr.  f.  Unters.  von  Nahr.-  und  Genussmitt,  257  (1904). 

1"  E.  von  Lippmann.  Ueber  Stickstoffhaltigen  Bestandtheile  aus  Riibensaften.  Ber. 
der  Dtsch.  chem.  Gesell.,  29,  2650  (1896). 

1^  E.  Shorey.     Xanthin  Bases  in  Sugar  Cane.     Journ.  Am.  Chem.  Soc,  21,  432  (1899). 
12  H.  Bressler.     Ueber  die  Bestimmung  der  Nucleinbasen  im  Safte  von  Beta  vulgaris. 
Zeitschr.  fiir  physiol.  Chem.,  41,  535  (1904). 

13  F.  Wohler  und  F.  Frerichs.  Ueber  die  Veranderungen,  welche  namentlich  organische 
Stoffe  beim  Uebergang  in  den  Harn  erleiden.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  65, 
335  (1848). 

I*  J.  LieMg^    Animal  Chemistry,  or  Organic  Chemistry  in  its  Application  to  Physiology 
and  Pathology.     Transl.  of  W.  Gregory.     1843  ed.  by  J.  Webster,  Cambridge. 
"  C.  Lehmann.     Physiologische  Chemie.     Vol.  I,  2d  ed.  (1853). 


Physiology  113 

between  the  purin  bases  and  uric  acid.  This  method  will  be 
simpler,  and  the  true  explanation  of  the  facts  on  which  the  old 
theory  was  based  will  be  clearer. 

In  1853,  Virchow^  found  that  the  excretion  of  uric  acid  is 
increased  in  leukemia.  He  thought  that  this  might  be  due  either 
(a)  to  a  decreased  power  of  internal  respiration  on  account  of 
lack  of  red  blood  corpuscles,  or  (6)  to  an  oxidation  of  hypoxan- 
thin  formed  by  increased  activity  of  the  spleen.  The  first  hy- 
pothesis is  based  entirely  on  the  old  theory  of  uric  acid  formation. 
It  will  be  considered  later.  The  second  hypothesis  is  based  on 
the  discovery  of  hypoxanthin  in  the  watery  extract  of  the  spleen,^ 
and  also  in  leukemic  blood  ^  by  Scherer,  and  on  the  close  chemical 
relationship  shown  by  him  ^  to  exist  between  hypoxanthin  and 
uric  acid.  In  a  later  article  *  Scherer  confirmed  his  earlier  dis- 
covery and  found  in  leukemic  blood  not  only  hypoxanthin,  but 
also  uric  acid.  Ranke,^  likewise,  who  found  the  excretion  of 
uric  acid  increased  in  leukemia,  attributed  it  to  the  hypoxanthin 
produced  by  the  activity  of  the  spleen.  He  believed  that  nor- 
mally the  uric  acid  comes  from  the  spleen.  Meissner,**  too,  be- 
lieved that  the  uric  acid  is  derived  normally  from  the  xanthin 
bases  of  the  tissues. 

Salkowski  ^  maintained  that  if  the  increased  excretion  of  uric 
acid  in  leukemia  is  due  to  defective  oxidation,  other  products 
of  defective  oxidation  should  be  found  in  the  urine.  He  could 
find,  however,  no  products  which  could  not  be  explained  by 
assuming  an  increased  activity  of  the  spleen.^  He  therefore 
expressed  the  view  that  the  increased  secretion  of  uric  acid  in 
leukemia  which  had  been  noticed  by  Virchow/  Thierfelder  and 

1  R.  Virchow.  Zur  pathologischen  Physiologie  des  Blutes.  Virchow's  Archiv,  5,  43 
(1853). 

2  Scherer.  Ueber  einen  im  thierischen  Organismus  vorkommenden  dem  Xanthinoxyd 
verwandten  Korper.     Liebig's  Ann.  der  Chem.  u.  Pharm.,  73,  328  (1850). 

3  Ibid.  Untersuchungen  iiber  das  Blut  bei  Leukamie.  Verhandl.  der  physik. 
mediz.  Gesellsch.  zu  Wurzburg,  2,  321   (1851). 

*  Ibid.  Beitrag  zur  Geschichte  der  Leukamie.  Chemische  Untersuchungen  des 
Blutes.     Verhandl.  der  physik.  mediz.  Gesellsch.  zu  Wurzburg,  7,  123  (1856). 

5  H.  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidung  der  Harnsaure  beim 
Menschen.     Miinchen,  1858. 

8  G.  Meissner.  Beitrage  zur  Kenntnis  des  Stoffwechsels  im  thierischen  Organismus. 
Zeitschr.  fur  rationelle  Med.,  3  Reihe,  31,  234  (1868). 

'  E.  Salkowski.  Beitrage  zur  Kenntniss  der  Leukamie.  Virchow's  Archiv,  50,  174 
(1870). 

*  Ibid.  Weitere  Beitrage  zur  Kenntniss  der  Leukamie.  Virchow's  Archiv,  52, 
58  (1871). 


114    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Uhle/  H.  Ranke,2  Parkes,^  Mosler/  Berell;^  Schultzer;  Pettenkofer 
and  Voit/  Jacubasch,*  Reichhardt/  and  Hofmann/°  was  due  to 
an  oxidation  of  the  hypoxanthin  coming  from  increased  activity 
of  the  spleen. 

The  view  that  the  high  excretion  of  uric  acid  in  leukemia  is  due 
to  an  oxidation  of  hypoxanthin  present  in  the  blood  through 
increased  activity  of  the  spleen  did  not  seem  to  explain  the  physio- 
logical source  of  uric  acid,  although  Ranke  and  Meissner  believed 
that  even  normally  uric  acid  is  derived  from  hypoxanthin.  It 
was  not  believed  that  hypoxanthin  is  present  in  the  tissues  of 
the  body  and  in  the  food  in  large  enough  quantities  to  serve  as 
source  for  all  the  uric  acid  excreted.  In  any  case,  however,  the 
ultimate  source  of  uric  acid  was  still  supposed  to  be  proteid,  for 
hypoxanthin  was  considered  a  decomposition  product  of  proteid. 
Thus,  Salomon  "  and  Chittenden  ^^  obtained  hypoxanthin  and 
xanthin  by  the  action  of  pancreas  ferment  on  fibrin.  Although 
Drechsel  ^^  had  suggested  that  the  small  amount  of  xanthin  bases 

1  T.  Thierfelder  und  J.  Uhle.  Ein  Fall  von  Leukamie.  Arch.  f.  physiol.  Heilk.,  15, 
441   (1856). 

2  H.  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidung  der  Harnsaure  beim 
Menschen.     Miinchen,  1858.     Schmidt's  Jahrb.,  104,  22  (1859). 

aParkes.     The   Composition   of   Urine.     London,    3.31    (1860). 

^  E.  Mosler  und  W.  Korner.  Zur  Blut  und  Harnanalyse  bei  Leukamie.  Virchow's 
Archiv,  25,  142  (1862).     Also, 

F.  Mosler.  Zur  Diagnose  der  henalen  Leukamie  und  der  chemischen  Beschaffenheit 
der  Transudate  und  Secrete.     Virchow's  Archiv,  37,  43  (1868). 

5  C.  Berell.  Zur  Kasuistik  der  Leukamie.  Schmidt's  Jahrb.,  142,  167  (1869)  from 
Medical  Times  and  Gazette,  March  14,  p.  284  (1868). 

8  Steinberg.     Ueber   Leukamie.     Inaug.   Dissert.,   Berlin,    1868. 

'  M.  V.  Pettenkofer  und  C.  Voit.  Ueber  den  Stoffverbrauch  bei  einem  leukamischen 
Manne.     Zeitschr.  fiir  Biol.,  5,  319  (1869). 

8  H.  Jacubasch.  Beitrage  zur  Harnanalyse  bei  lienaler  Leukamie.  Virchow's  Archiv, 
43,   196   (1868). 

'  E.  Reichhardt.  Blut  und  Harn  bei  Leukamie.  Jenaische  Zeitschr.  f.  Medizin  und 
Naturwissenschaf ten ,  5,  389  (1870). 

1"  K.  Hofmann.  Ilarnbeschaffenheit  bei  Leukamie  lienalis.  Wien  Med.  Wochenschrift, 
20,  981  (1870),  and  20,  1036  (1870). 

"  G.  Salomon.  Bildung  von  Xanthinkorper  aus  Eiweiss  durch  Pancreasverdauung. 
Ber.  der  Dtsch.  chem.  Gesell.,  11,  574  (1878). 

Ibid.  Ueber  die  Verbreitung  und  Entstehung  von  Hypoxanthin  und  Milch- 
saure  im  tierischen  Organismus.     Zeitschr.  fiir  physiol.  Chem.,  2,  65  (1878). 

H.  Krause  und  G.  Salomon.  Weitere  Mittheilungen  liber  die  Bildung  von  Xanthin- 
korpern  aus  Eiweiss.     Ber.  der  Dtsch.  chem.  Gesell.,  12,  95  (1879). 

G.  Salomon.  Ueber  die  Entstehung  von  Hypoxanthin  aus  Eiweisskorpern.  Ber. 
der  Dtsch.  chem.  Gesell.,  13,  1160  (1880). 

^-  R.  Chittenden .  On  the  Formation  of  Hypoxanthin  from  Albumin.  Journ.  of 
Physiol.  2,  28  (1879-80),  and  Untersuchungen  des  physiologische  Instituts  der  Univers. 
Heidelberg,  Bd.  2.     Heft  4. 

13  E.  Drechsel.  Zur  Frage  nach  der  Entstehung  von  Hypoxanthin  aus  Eiweisskorpern. 
Ber.  der  Dtsch.  chem.  Gesell.,  13,  240  (1880). 


Physiology  115 

might  come  from  impurities  such  as  the  white  blood  corpuscles 
enclosed  by  the  fibrin,  yet  even  in  18S2  Salkowski  and  Leube  ^ 
considered  hypoxanthin  a  decomposition  product  of  proteid. 

About  1880  KosseP  began  to  study  the  nucleins  which  had 
been  discovered  by  Miescher^  ten  years  before.  In  his  first 
research  on  the  subject,  Kossel  found  hypoxanthin  as  a  decom- 
position product  of  the  nucleins.  As  a  result  of  this  and  later 
researches,*  he  soon  came  to  the  conclusion  that  the  nucleins  alone 
are  the  physiological  source  of  the  purin  bases.  As  a  result  of 
the  determination  of  the  free  purin  bases  and  those  combined  in 
nucleins  in  the  tissues,  he  found  that  the  purin  bases  are  present 
in  much  larger  quantities  than  had  previously  been  supposed.'^ 
He  suggested  that  the  purin  bases  might  be  the  physiological 
antecedents  of  uric  acid  and  showed  that  the  objection  that  these 
bases  are  not  present  in  the  tissues  in  large  enough  c^uantities 
to  serve  as  the  physiological  source  of  uric  acid  could  no  longer 
hold.  Salomon  soon  admitted  that  his  earlier  belief  that  the 
xanthin  bases  can  be  derived  from  albumin  is  erroneous.*^ 

Kossel^  later  showed  that  the  muscles  of  those  animals,  the 
chief  end  product  of  whose  nitrogenous  metabolism  is  uric  acid, 
are  richer  in  purin  bodies  than  the  muscles  of  mammals,  and  that 
leukemic  blood  is  richer  in  hypoxanthin  than  normal  blood. 
Previous  to  this  Chrzonszczewski  ^  and  Pawlinoff^  had  shown 
that  in  the  tissues  of  birds  whose  ureters  have  been  tied,  the  uric 
acid  concretions  are  abundant  near  the  cell  nuclei.  Benecke  ^" 
and  Senator  *^  had  expressed  the  idea  that  urea  and  uric  acid  are 

1  Salkowski  und  Leube.     Die  Lehre  vom  Harn,  pp.  98,  99,  106.     Berlin  (1882). 

2  A.  Kossel.     Ueber  das  Nuclein  der  Hefe.     Zeitschr.  fiir  physiol.  Chem.,  .3,  284  (1879). 

3  Miescher.     Medic-ohem.     Untersuchungen  von  Hoppe-Seyler,  441. 

^  A.  Eossel.  Ueber  die  Herkunft  des  Hypoxanthins  in  den  Organismen.  Zeitschr.  fiir 
physiol.  Chem.,  5,  152  (1881). 

Ihid.     Ueber  das  Nuclein  der  Hefe.     Zeitschr.  f.  physiol.  Chem.,  4,  290  (1880). 

Ibid.  Ueber  Xanthin  und  Hypoxanthin.  Zeitschr.  fiir  physiol.  Chem.,  6,  422 
(1882). 

Ihid.     Zur  Chemie  des  Zellkernes.     Zeitschr.  fiir  physiol.  Chem.,  7,  7  (1882-3). 

5  Ihid.  Ueber  die  Verbreitung  des  Hypoxanthins  im  Thier-  und  Pflanzenreich. 
Zeitschr.  fur  physiol.  Chem.,  5,  267  (1881). 

s  G.  Salomon.  Zur  Physiologic  der  Xanthinkorper  Vortrag  gehalten  in  der  physiol. 
Gesell.  zu  Berlin  am  20  mai,  1881.     Du  Bois  Archiv,  361  (1881). 

'■  A.  Kossel.     Zur  Chemie  des  Zellkernes.     Zeitschr.  fiir  physiol.  Chem.,  7,  7  (1882). 

*  N.  Chrzonszczewski.  Ueber  der  Ursprung  der  Lymphgefasse.  Virchow's  Archiv,  35 
174  (1866). 

9  C.  Pawlinoff.  Die  Bildungsstatte  der  Harnsaure  in  Orgauismus.  Virchow's  Archiv, 
62,  57  (1S75). 

"^  Benecke.     Grundlinien  der  Pathologie  des  Stoffwechsels  (1874). 

"  Senator.  Ueber  Podagra.  Ziemssen's  Handbuch  der  spez.  Pathol,  und  Therapie 
(1875). 


116    The  Chemistry    Physiology,  and  Pathology  of  Uric  Acid 

derived  from  different  sources.  They  did  not,  however,  state 
just  what  they  beheved  to  be  the  source  of  uric  acid.  Kerner,^ 
the  first  to  attempt  direct  feeding  experiments  with  a  purin  base, 
fed  guanin  to  rabbits  but  could  not  observe  any  increase  in  the 
excretion  of  uric  acid. 

Baginsk)"^  then  attempted  direct  feeding  experiments.  He 
fed  hypoxanthin  to  dogs,  but  could  observe  no  increase  in  the 
excretion  of  uric  acid,  although  the  hypoxanthin  did  not  appear 
in  the  urine.  Nencki  and  Sieber^  likewise  could  observe  no 
increased  excretion  of  uric  acid  after  feeding  xanthin  to  dogs, 
but  there  was  an  increase  of  the  excretion  of  urea.  The  xanthin 
did  not  reappear  in  the  urine.  This  work  was  confirmed  a  dozen 
years  later  by  Kriiger  and  Salomon.^ 

Ebstein^  expressed  the  view  that  the  negative  results  obtained 
by  feeding  purin  bases  to  animals  with  the  expectation  of  obtain- 
ing an  increase  in  the  excretion  of  uric  acid  is  due  to  the  fact 
that  some  special  conditions  lacking  in  the  artificial  experiments 
determine  the  formation  of  uric  acid  normally  from  the  xanthin 
bases  of  the  body. 

Stadthagen"  repeated  the  feeding  experiments  and  attempted 
to  increase  the  uric  acid  excretion  by  feeding  purin  bodies.  He, 
likewise,  obtained  negative  results.  He  then  took  up  Ebstein's 
hypothesis  and  believed  it  possible  that  although  outside  the  body 
purin  bases  are  obtained  by  decomposition  of  nucleins,  yet  in  the 
body  uric  acid  itself  is  obtained  and  not  the  bases.  He  carried 
out  feeding  experiments,  giving  nucleins  instead  of  purin  bases. 
In  this  case,  too,  he  obtained  no  increase  in  the  excretion  of  uric  acid. 
At  first  he  believed  that  possibly  this  nuclein  artificially  obtained 
might  act  in  a  different  manner  from  the  living  nucleoproteid  in 
the  cell,  but  since  he  could  show  no  relation  between  the  uric 
acid  excretion  and  the  decomposition  of  cell  nuclei,  he  returned 

1  Kerner.  Ueber  das  Verhalten  des  Guanins.  Annal.  d.  Chem.  u.  Pharm.,  103,  249 
(1857). 

2  A.  Baginsky.  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxanthin. 
Zeitschr.  fiir  physiol.  Chem.,  8,  395  (1883). 

3  M.  Nencld  und  N.  Sieber.  Ueber  eine  neue  Methode  die  physiologische  Oxydation  zu 
messen  und  tiber  die  Einfluss  der  Gifte  und  Krankheiten  auf  dieselbe.  Pfliiger's  Archiv, 
31,  319  (1883). 

*  M.  Kriiger  und  G.  Salomon.  Die  Konstitution  des  Heteroxanthins  und  seine  physio- 
logische Wirkung.     Zeitschr.  fur  physiol.  Chem.,  21,  168  (1885). 

5  W.  Ebstein.     Die  Natur  und  Behandlung  der  Gicht,  98  (1882). 

6  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaure  in  verscheidenen  tierischen  Or- 
ganen,  ihr  Verhalten  bei  der  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  Stick- 
stoffbasen.     Virchow's  Archiv,  109,  390  (1887). 


Physiology  117 

to  the  old  view  that  the  uric  acid  is  derived  from  proteid.  Gum- 
lich  ^  later  repeated  these  niiclein  feeding  experiments,  and  proved 
that  the  nucleins  Avere  absorbed,  something  Stadthagen  had  not 
done,  but  still  found  no  increased  excretion  of  uric  acid.  He  did 
not,  however,  conclude  from  his  results  that  uric  acid  cannot  be 
derived  from  the  nucleins. 

Horbaczewski  ^  then  took  up  the  work.  He  found  that  on 
digesting  freshly  cut-up  spleen  with  defibrinated  blood  and  air, 
uric  acid  is  obtained.  The  amount  of  uric  acid  obtained  varies 
with  the  quantity  of  spleen  used  and  the  length  of  time  of  diges- 
tion. Blood  free  from  oxygen  does  not  act.  Therefore  the 
formation  of  uric  acid  is  probably  an  oxidation  process  in  part. 
Horbaczewski  expressed  the  view  that  the  uric  acid  comes  from 
the  lymphatic  elements  of  the  spleen,  a  fact  which  he  proved  later. 

In  a  second  article,  Horbaczewski^  showed  that  if  spleen  be 
digested  with  water  instead  of  with  blood,  purin  bases  instead  of 
uric  acid  are  obtained.  These  he  could  not  oxidize  to  uric  acid 
by  digestion  with  arterial  blood.  This  seemed  to  indicate  the 
truth  of  Stadthagen's  view  that  the  uric  acid  and  purin  bodies 
are  derived  from  a  common  antecedent,  but  that  the  purin  bases 
once  formed  cannot  be  oxidized  to  uric  acid  in  the  body.  If 
nuclein  be  used  instead  of  cut-up  spleen,  the  same  results  are 
obtained,  and  experiments  on  rabbits  and  man  showed  that 
administration  of  nuclein  with  the  food  gave  a  decided  increase 
in  the  amount  of  uric  acid  excreted.  The  negative  results  ob- 
tained by  Stadthagen  and  Kerner  were  attributed  by  Horbac- 
zewski to  the  use  of  dogs.  These  he  thinks  react  differently 
from  rabbits  and  man  in  respect  to  uric  acid  excretion. 

The  objection  of  Kossel  *  and  Wulff  ^  that  Horbaczewski  did  not 
have  an  accurate  method  of  separating  purin  bases  and  uric  acid 
and  consequently,  that,  instead  of  chiefly  uric  acid,  Horbaczewski 
might  have  obtained  chiefly  purin  bases  in  many  of  his  experi- 

'  G.  Gumlich.  Ueber  die  Aufnahme  der  Nucleine  in  den  theirischen  Organismus. 
Zeitschr.  fiir  physiol.  Chem.,  18,  508  (1894). 

2  Horbaczewski.  Untersuchungen  iiber  die  Entstehung  der  Harnsaure  im  Saugetheir- 
organismus.     Monatshefte  fiir  Ciieroie,  10,  624  (1S89). 

3  Ihid-  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xanthinbasen, 
sowie  der  Entstehung  der  Leukocytose  im  Saugetheirorganismus.  Monatshefte  fiir  Chemie, 
12,  221   (1891). 

••  H.  Kossel.  Ueber  Nucleinsaure.  Vortrag  gen.  in  d.  physiol.  Gesell.  zu  Berlin  am 
14  Oktober  (1892).     Du  Bois  Archiv,  157  (1893). 

'"  C.  Wulff.  Zum  Nachweiss  der  Harnsaure  in  den  Organen.  Zeitschr.  fiir  physiol. 
Chem.,    17,   634   (1893). 


118    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

ments  was  met  by  Horbaczewski/  who  declared  that  he  always 
had  either  uric  acid  entirel}^  or  purin  bases  entirely  as  end  products 
of-  digestion.  Later  ^  he  confirmed  his  results  by  using  a  more 
accurate  method  of  separation  for  uric  acid  and  purin  bases.  The 
results  of  Horbaczewski  were  completely  confirmed  by  Giacosa.' 
Spitzer  *  repeated  the  work  of  Horbaczewski.  He  found  that 
the  slight  bacterial  decomposition  which  Horbaczewski  found 
necessary  to  obtain  his  results  is  not  necessary.  Further,  he 
contested  the  idea  that  uric  acid  and  purin  bodies  come  from  a 
common  antecedent,  and  that  purin  bodies  once  formed  cannot 
change  to  uric  acid.  He  called  attention  to  the  Avork  of  Salomon  ^ 
and  Salkowski,^  who  found  purin  bases  in  extracts  of  liver  and 
spleen,  and  showed  that  this  gradually  disappears  and  changes 
to  uric  acid  on  digestion  with  blood  and  air.  Further,  he  showed 
that  if  weighed  amounts  of  xanthin  or  hypoxanthin  are  added  to 
the  mixture  of  blood  and  spleen  in  one  of  these  digestion  experi- 
ments, they  are  oxidized  to  uric  acid,  thus  giving  a  complete 
proof  that  purin  bases  can  act  as  antecedents  of  uric  acid  in  the 
animal  body.  Guanin  and  adenin  could  hkewise  be  changed  to 
uric  acid,  but  not  in  such  large  quantities  as  xanthin  and  hypo- 
xanthin. He  found  that  if  the  spleen  or  liver  were  left  out  in  the 
experiment  that  blood  alone  could  not  change  the  bases  to  uric 
acid.  There  is  present  in  those  organs  something  necessary  to 
carry  on  the  oxidation.  This  work  was  further  confirmed  by 
Weintraud,^  Mayer ,^  Bohland,*^  Richter,^"  Wiener,"  and  others,  so 

I  Horbaczewski.  Bemerkungen  zum  Vortrage  des  Herrn  Kossel:  Ueber  Nucleinsaure. 
Du  Bois  Archiv,  109  (1893). 

-  Ihid.  Ueber  die  Trennung  der  Harnsaure  von  den  Xanthinbasen.  Zeitschr.  f .  physiol. 
Chem.,  18,  341  (1894). 

^  P.  Giacosa.  Ueber  die  Bildung  der  Harnsaure  im  Organismus.  Maly's  Jahresb.  iiber 
die  Fortschritte  der  Thierchemie,  21,  182  (1891),  and  Weiner  Med.  Blatter,  1890,  No.  32. 

^  W.  Spitzer.  Die  Ueberfiihrung  von  Nuclembasen  in  Harnsauren  durch  die  Sauer- 
stoffubertragende  Wirkung  von  Gewebsausziigen.     Pfliiger's  Archiv,  76,  192  (1899). 

''  G.  Salomon.  Zur  Physiologic  der  Xanthinkorper.  Vortrag  geh.  in  d.  physiol.  Gesell. 
zu  Berlin  am  20  Mai,  1881.     Du  Bois  Archiv,  361  (1881). 

6  E.  Salkowski.  Ueber  Autodigestion  der  Organe.  Zeitschr.  fiir  klin.  Medizin,  17, 
SuppL,  77  (1890). 

^  W.  Weintraud.  Ueber  die  Einfluss  des  Nukleins  der  Nahrung  auf  die  Harnsaure- 
bildung.     Berl.   klin.    Wochenschrift,    32,   405  (1895). 

*  P.  Mayer.  Ueber  den  Einfluss  von  Nucle'in  und  Thyreoidinfiitterung  auf  die  Harn- 
saureausscheidung.     Deutsche  Med.  Wochenschrift,  22,  186  (1896). 

'^  Bohland.  Ueber  den  Einfiuss  einiger  Arzneimittel  auf  die  Bildung  und  Ausscheidung 
der  Harnsaure.     Miinchener  Mediz.  Wochenschrift,  46,  505  (1899). 

1"  P.  Eichter.  Ueber  die  Harnsaureausscheidung  und  Leukocytose.  Zeitschr.  fiir 
kUn.  Medizin,  27,  290  (1895). 

II  H.  Wiener,  Ueber  Zersetzung  und  Bildung  der  Harnsaure  im  Tierkorper.  Ver- 
handl.  des  17t  Kongr.  f.  innere  Med.,  622  (1899),  and  Arch,  fiir  exp.  Path.  u.  Pharmak., 
42,  375  (1899). 


Physiology  119 

that  there  is  now  no  question  that  nucleoproteids,  nucleins,  and 
purin  bases  can  serve  as  sources  for  uric  acid  in  the  animal  organ- 
ism. Only  Kutscher  and  Seeman  ^  have  doubted  in  recent  times 
that  uric  acid  does  not  come  from  nucleins.  They  base  their 
objection  on  the  fact  that  they  obtained  urea  and  imido  urea,  but 
no  uric  acid  in  the  oxidation  of  nucleic  acid  by  calcium  perman- 
ganate. This,  of  course,  cannot  be  considered  an  objection  in 
view  of  the  results  of  direct  experiments;  besides,  Burian^  has 
shown  that  calcium  permanganate  oxidizes  uric  acid  to  urea  and 
oxalic  acid,  and  therefore  any  uric  acid  formed  from  the  purins 
of  the  nucleic  acid  in  the  experiments  of  Kutscher  and  Seeman 
is  destroyed. 

Uric  Acid  derived  from  the  Nucleoproteids  and  Purins 
OF  THE  Body.  Uric  Acid  from  the  Leucocytes.  —  As  a  result  of  his 
work,  Horbaczewski  ^  expressed  the  view  that  just  as  fresh  blood 
acts  on  the  lymphatic  elements  of  the  spleen  to  form  uric  acid,  so 
we  might  by  analogy  believe  that  in  the  living  organism  the  blood 
acts  on  its  own  leucocytes  to  form  uric  acid.  He  explained  the 
increased  excretion  of  uric  acid  in  leukemia  by  assuming  that  the 
large  number  of  leucocytes  in  the  blood  in  this  disease  gives  rise, 
by  the  oxidizing  action  of  the  blood,  to  a  correspondingly  large 
amount  of  uric  acid.  He  called  attention  to  the  coincidence  of 
the  digestive  leucocytosis  and  the  increased  excretion  of  uric 
acid  shown  by  Ranke  *  to  take  place  after  ingestion  of  large 
quantities  of  proteid  food.  He  noted,  too,  that  the  blood  of 
children  is  richer  in  leucocytes  than  that  of  adults,  that  the  blood 
of  men  is  richer  in  leucocytes  than  that  of  w^omen,  that  the  blood 
of  well-nourished  individuals  is  richer  in  leucocytes  than  the 
blood  of  poorly  nourished  ones,  and  that,  correspondingly,  chil- 
dren excrete  relatively  more  uric  acid  than  adults,  men  excrete 
more  uric  acid  than  women,  and  well-nourished  individuals 
excrete  more  uric  acid  than  poorly  nourished  ones. 

1  F.  Kutscher  und  Seeman.  Die  Oxydation  der  Thymusnukleinsaure  mit  Calciumper- 
manganate.     Eer.  der  Dtsch.  chem.  GeselL,  36,  3023  (1903).     Also 

Ueber  die  Oxydation  der  Hefenukleinsaure  mit  Kalziumpermanganate.  Zentralbl. 
fiir  Physiol.,  17,  715  (1904). 

'R.  Burian.  Zu  den  Versuchen  von  Kutscher  und  Seemann  iiber  die  Oxydation 
dor  Nukleinsauren  mit  Caloiumpermanganate.     Zeitschr.  fiir  physiol.  Chem.,  43,  494  (1905). 

3  J.  Horbaczewski.  LJntersuchungen  iiber  die  Entstehung  der  Harnsaure  im  Sauge- 
theirorganismus.     Monatshefte  fiir  Chemie,   10,  624  (1SS9). 

*  Ranke.  Beobachtungen  und  Versuche  iiber  die  .-Vusscheidung  der  Harnsaure.  Habil- 
itationsschrift,  Mtinchen  (1858). 


120    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

In  a  second  article  ^  Horbaczewski  stated  his  belief  that  the 
formation  of  uric  acid  is  an  expression  of  the  decomposition  of 
tissues  rich  in  nuclein.  Since  the  tissues  of  the  body  which  are 
rich  in  nucleins,  witli  the  exception  of  the  leucocytes,  do  not 
undergo  rapid  metabolism,  that  is  to  say,  are  not  quickly  formed 
and  quickly  decomposed,^  Horbaczewski  assumed  that  the  uric 
acid  excreted  by  mammals  comes  from  a  decomposition  of  leu- 
cocytes. He  reiterated  what  he  said  in  his  earlier  article  in  con- 
firmation of  this  view  and  added  new  arguments.  In  regard  to 
the  coincidence  of  the  digestive  leucocytosis  and  the  increased 
excretion  of  uric  acid  after  meals,  he  showed  that  neither  is  so 
marked  after  eating  vegetable  food  as  after  eating  meat,  and 
that  in  certain  diseases  in  which  the  digestive  leucocytosis  is 
missing,  there  is  no  increased  excretion  of  uric  acid  after  meals. 
He  stated  that  when  this  digestive  leucocytosis  disappears,  the 
leucocytes  serve  to  build  up  the  tissues  of  the  body,  or  to  form, 
perhaps,  red  blood  corpuscles,  but  that  in  any  case,  the  nuclein 
in  the  leucocytes  decomposes  and  gives  uric  acid  as  one  of  its 
decomposition   products. 

Horbaczewski  then  studied  the  action  of  drugs  on  leucocytosis 
and  uric  acid  excretion.  Ranke,^  Kerner,*  Prior ,^  and  Kumagawa  ^ 
had  found  that  quinine  decreases  the  excretion  of  uric  acid,  and 
Binz  ^  had  found  that  it  decreases  the  number  of  leucocytes  in  the 
blood.  Chittenden  ^  had  found  that  antipyrin  decreases  the 
excretion  of  uric  acid.  Umbach''  did  not  find  antipyrin  to  have 
any  effect  on  the  excretion  of  uric  acid,  while  Kumagawa,"  on 
the  other  hand,  found  it  to  increase  the  excretion  of  uric  acid. 


1  J.  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xan- 
thinbasen,  sowie  der  Entstehung  der  Leucocytose  im  Saugethierorganismus.  Monatshefte 
fiir  Chemie,  12,  221  (1891). 

2  Voit.     Physiol,  d.  allg.     Stoffwechsels  und  d.  Ernahrung,  1881,  p.  274. 

3  Ranke.  Beobachtungen  und  Versuche  fiber  die  Aussclieidung  der  Harnsaure.  Ha- 
bilitationsschrift,  Munchen   (1858). 

*  G.  Kerner.  Beitrage  zur  Kenntniss  der  Chininresorption.  Pfluger's  Archiv,  3,  93 
(1870). 

5  Prior.  Ueber  den  Einfluss  des  Chinin  auf  den  Stoffwechsel  des  gesunden  Organismus. 
Pfluger's  Archiv,  34,  237  (1884). 

^  M.  Kumagawa.  Ueber  die  Wirkung  einiger  antipyretische  Mittel  auf  den  Eiweis- 
sumsatze  im  Organismus.     Virchow's  Archiv,  113,  134  (1888). 

'  Binz.     Das  Chinin,  etc.     Berlin,  1875,  p.  12. 

8  R.  Chittenden.  Ueber  den  Einfluss  von  Urethan,  Antipyrin,  und  Antifibrin  auf  den 
Eivceissumsatz.     Zeitschr.    fur    Biol.,    25,    496    (1889). 

9  M.  Umbach.  Ueber  den  Einfluss  des  Antipyrins  auf  die  Stickstoffausscheidung . 
Arch,  fur  exp.  Path.  u.  Pharmak.,  21,  161  (1886). 


Physiology  121 

Antifebrin  had  been  found  by  Chittenden/  and  pilocarpin  by 
Mares/  to  increase  the  excretion  of  uric  acid.  Horbaczewski 
repeated  this  work  and  found  that  quinine  and  atropin  decrease 
the  excretion  of  uric  acid  and  hkewise  the  number  of  leucocytes 
in  the  blood,  and  that  pilocarpin  increases  the  excretion  of  uric 
acid  and  the  number  of  leucocytes  in  the  blood.  On  the  other 
hand,  antipyrin  and  antifebrin  increase  the  number  of  leucocytes 
but  decrease  the  uric  acid  excretion.  Horbaczewski  explained 
the  action  of  antipyrin  and  antifebrin  by  assuming  that  they 
cause  a  decreased  decomposition  of  leucocytes,  thus  decreasing 
the  excretion  of  uric  acid  and  increasing  the  quantity  of  leucocytes 
present. 

For  further  confirmation  of  his  theory,  Horbaczewski  then 
turned  to  pathological  conditions.  The  increased  excretion  of 
uric  acid  in  leukemia  seemed  to  be  in  accord  with  his  theory. 
The  relation  between  the  decomposition  of  tissue  and  the  increased 
excretion  of  uric  acid  found  by  Frankel  and  Rohmann^  in 
phosphorous  poisoning  seemed  plain  from  the  standpoint  of  this 
theory.  The  increased  excretion  of  uric  acid  in  fevers  noticed 
by  Carlo*  and  Baftalowskj^,^  and  in  inanition  and  cachexia  is, 
according  to  Horbaczewski,  an  expression  of  the  decomposition 
of  tissue  rich  in  nuclein.  Frey  and  Heiligenthal  found  that  hot 
air  baths  increase  the  excretion  of  uric  acid,  and  Horbaczewski 
found  that  they  cause,  likewise,  increase  of  the  leucocytes  of 
the  blood. 

Horbaczewski  believed  that  the  uric  acid  excreted  comes 
almost  exclusively  from  the  leucocytes  of  the  blood,  and  that  the 
nuclein  in  the  food  need  not  necessarily  be  assumed  to  decompose 
and  oxidize  to  uric  acid,  but  that  it  may  act  like  certain  drugs  to 
increase  the  number  of  leucocytes  and  thus  indirectly  increase 
the  uric  acid  excretion.  The  fact  that  the  intensity  of  increase 
in  the  excretion  of  uric  acid  and  the  increase  in  the  number  of 

1  R.  Chittenden.  Ueber  den  Einfluss  von  Urethan,  Antipyrin,  und  Antifebrin  auf  den 
Eiweissumsatz.     Zeitschr.  fiir  Biol.,  25,  496  (1898). 

^  F.  Mares.  Sur  Torigine  de  I'acide  urique  chez  I'homme.  Archives  slaves  de  Biologie, 
3,  207  (1888). 

3  Fraenkel  und  Rohmann.  Phosphorvergiftung  bei  Hiihnern.  Zeitschr.  fiir  physiol. 
Chem.,  4,  439  (1880). 

^  Carlo.  Ueber  den  Einfluss  des  Fiebers  und  der  Inanition  auf  die  Ausscheidung  der 
Harnsaure  und  der  ubrigen  wesentlichen  Harnbestandtheile.  Preisschrift  Gottingen, 
(1888). 

5  Baftalowsky.  Die  Methoden  der  Harnsaurebestimmungen.  Maly's  Jahresb.  iiber 
die  Fortschritte  der  Thierchem.,  18,  128  (1889). 


122    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

leucocytes  of  the  blood  is  not  parallel,  and  that  we  may  have  a 
large  quantity  of  leucocytes  in  the  blood  and  a  relatively  small 
increase  in  the  excretion  of  uric  acid,  and,  vice  versa,  he  explained 
by  saying  that  the  size  of  the  individual  leucocytes  and  the  amount 
of  nuclein  in  them  is  variable. 

The  view  that  the  uric  acid  is  derived  from  the  leucocj^tes  had 
been  expressed  by  Benecke  ^  many  years  before  Horbaczewski's 
article  appeared,  but  the  latter  seems  to  have  brought  more  facts 
to  uphold  his  theory  or  to  have  expressed  it  in  a  more  decided 
manner,  for  he  is  given  the  credit  of  being  the  author  of  the  theory 
by  practicall}^  all  writers. 

A  number  of  physiologists  published  results  which  seemed  to 
confirm  the  view^s  of  Horbaczewski.  Sticker,^  Frankel,^  and 
Gumprecht,*  for  example,  found  that  in  leukemia  there  is  a 
parallelism  between  the  number  of  leucocytes  in  the  blood  and 
the  excretion  of  uric  acid,  and  Gumprecht  showed  that  in  leu- 
kemia there  is  also  an  increased  decomposition  of  leucocytes  as 
well  as  an  increased  formation.  Dunin  and  St.  Nowaczek^  found 
that  in  pneumonia  there  is  an  increased  excretion  of  uric  acid 
with  the  increased  leucocytosis.  This  had  been  noticed  earlier 
by  Gardes."  Kiihnau^  found  an  increased  excretion  of  uric  acid 
in  leukemia,  pneumonia  at  the  crisis,  and  in  other  diseases  in 
which  there  is  an  increase  of  leucocytes,  as  well  as  in  cases  where 
the  leucocytosis  is  brought  about  artificially.  This  author  found, 
too,  that  as  the  leucocytosis  disappears  in  pneumonia,  the  uric 
acid  excretion  increases,  a  fact  which  he  thought  Indicated  that 
the  uric  acid  is  derived  from  these  decomposed  leucocytes.  Pope,* 
however,  believed  that  the  increased  excretion  of  uric  acid  in 
pneumonia  comes  from  the  leucocytes  of  the  exudate,  since  the 

1  Cited  by  Girandeau.  Note  sur  un  cas  de  Leukocythfemie  splenique.  Arch,  de  physi- 
ologie  norm,  et  pathoL,  No.  8,  1884.     Girandeau  does  not  give  the  original  reference. 

2  G.  Sticker,  Beitrage  zur  Pathologie  und  Therapie  der  Leukarnie.  Zeitschr.  fur 
kUn.  Medizin,  14,  80  (1888). 

3  A.  Frankel.  Ueber  akute  Leukamie.  Deutsche  med.  Wochenschrift,  vol.  21,  pp. 
639,  663,  676,  699,  and  712  (1895). 

^  Gumprecht.  Leak ocytenzerf all  im  leukamischen  Blute.  Verhandlungen  des  17 
Kongr.  fiir  innere  Medizin,  314  (1896). 

s  T.  Dunin  und  St.  Nowaczek.  Ueber  Harnsaureausscheidung  bei  crouposer  Pneu- 
monie.     Zeitschr.  fur  klin.  Medizin,  32,  1  (1897). 

6  Gardes.  Ueber  Stickstoff  und  Harnsaureausscheidung  bei  verscheidenen  Krank- 
heiten   (1890). 

'  W.  Kiihnau.  E.xperimentelle  und  klinische  Untersuchungen  liber  das  Verhaltniss 
der  Harnsaureausscheidung  zur  Leukocytose.     Zeitschr.  ftir  klin.  Med.,  28,  534  (1895). 

s  C.  Pope.  Zur  Kenntniss  der  Beziehungen  zwischen  Hyperleukocytose  und  Allo- 
xurkorperausscheidung.     Centralblatt  fiir  innere  Medizin,  20,  657  (1899). 


Physiology  123 

increased  excretion  seems  to  occur  after  the  absorption  of  the 
exudate  and  not  when  the  leucocytosis  is  present. 

Daniel^  found  that  quinine,  which  lowers  the  number  of  leu- 
cocytes, prevents  also  an  increased  excretion  of  uric  acid  after 
thymus  feeding.  Since  thymus  feeding  alone  causes  an  increased 
excretion  of  uric  acid,  Daniel  explained  his  results  by  saying 
that  thymus  feeding  causes  a  hyperleucocytosis,  and  that  the 
hyperleucocytosis  causes  increased  excretion  of  uric  acid.  When 
the  hyperleucocytosis  is  prevented  from  occurring  by  the  ciuinine, 
the  increased  excretion  of  uric  acid  does  not  take  place.  It  has 
been  shown  by  Ranke,^  however,  that  quinine  likewise  causes  a 
decreased  excretion  of  uric  acid,  so  that  in  Daniel's  experiments 
the  decreased  excretion  of  uric  acid  by  quinine  merely  neutralizes 
the  increased  excretion  usually  brought  about  by  thymus  feeding. 
As  a  matter  of  fact,  Burian  and  Schur^  showed  this  to  be  the  case 
by  calculation  from  Daniel's  results. 

]\Iilroy  and  Malcolm  ^  found  that  after  thymus  feeding  the  excre- 
tion of  phosphorus  was  increased  more  than  could  be  explained 
by  the  assumption  that  it  comes  from  a  direct  decomposition  and 
oxidation  of  the  thymus  nuclein.  They  looked  upon  this  fact 
as  a  confirmation  of  Horbaczewski's  view  that  the  nuclein  merely 
increases  the  decomposition  of  the  leucocytes.  The  PoO,,  excreted, 
however,  is  not  a  measure  of  the  absorption  of  nuclein.  Other 
factors  come  into  play.  Kiihnau,'^  for  example,  observed  in 
malaria  an  increased  excretion  of  uric  acid  and  at  the  same  time 
a  decreased  excretion  of  PjOj.  The  same  thing  occurred  in  the 
metabolism  of  an  animal  poisoned  with  pyrogallol.  Jacob  and 
Bergell  ^  noted  that  there  is  a  retention  of  PoOj  by  the  body  if  the 
food  is  poor  in  phosphorus.  These  authors  found  an  increased 
excretion  of  uric  acid  after  feeding  spleen  to  an  anemic  patient, 
but  found  that  a  large  part  of  the  phosphorus  from  the  spleen 
nuclein  was  retained.     On   feeding  nuclein  to  a  gouty  patient, 

1  Daniel.     Inaug.  Dissert.,  Bonn  (189S). 

2  Ranke,  H.  Beobachtungen  und  Versuche  tiber  die  Ausscheidung  der  Harnsiiure  bei 
Menschen.     Miinchen    (1858). 

3  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.   1.  Mitteilung.     Pfliiger's  Archiv,   80,   241   (1900). 

*  T.  Milroy  and  .1.  Malcolm.  The  Metabolism  of  the  Nucleins  under  Physiological  and 
Pathological  Conditions.     Journ.  of  Physiol.,  23,  217  (1899). 

■''  W.  Kiihnau.  Ueber  das  Verhalten  des  Stoffwechsels  und  der  weissen  Blutelemente 
bei  Blutdissolution.     Dtsch.  Arch.  f.  klin.  Med.,  58,  339  (1897). 

"  P.  Jacob  und  P.  Bergell.  Ueber  den  Einfluss  nukleinhaltiger  Nahrung  auf  Blut  und 
Stoffwechsel  unter  besonderer  Berucksichtigung  des  Phosphorsaurestoffwechsels.  Zeitschr. 
fiir  kUn.  Med.,  35,  171  (1898). 


124   The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Vogt  ^  observed  that  the  phosphorus  from  the  nuclein  was  excreted 
very  quickly,  the  uric  acid  only  later.  The  phosphorus  excretion 
depends  somewhat,  too,  on  the  excretion  of  calcium.^ 

Williamson  ^  thinks  he  has  shown  a  relationship  between  uric 
acid  excretion  and  leucolysis. 

The  view  of  Horbaczewski  that  an  increased  excretion  of  uric 
acid  might  take  place  without  a  coincident  leucocytosis,  provided 
that  the  increased  uric  acid  came  from  the  decomposition  of 
leucocytes  especially  rich  in  nucleoproteid,  had  a  possible 
confirmation  in  the  work  of  Neusser.*  This  author  found  that 
in  gout  and  certain  other  diseases  there  were  granules  around 
the  nuclei  of  the  leucocytes  which  colored  with  basic  dj^es.  He 
interprets  them  as  an  overproduction  of  nuclear  material.  We 
shall  see  later,  however,  that  Neusser's  results  have  been 
questioned. 

Bohland^  confirmed  the  work  of  Horbaczewski,  showing  the 
influence  of  certain  drugs  on  the  excretion  of  uric  acid,  but  gave 
his  results  a  different  interpretation.  He  believes  that  under  the 
influence  of  pilocarpin  and  sodium  salicylate  more  uric  acid  comes 
from  the  decomposition  of  the  nucleoproteid  than  normally, 
w^hile  by  using  atropin,  tannic  acid,  and  chinin  more  purin  bases 
are  formed,  or  more  uric  acid  is  oxidized  to  allantoin  or  urea. 

On  the  other  hand,  before  the  publication  of  Horbaczewski's 
theory,  Girandeau  ^  studied  the  leucocytosis  and  the  excretion  of 
uric  acid  in  leukemia,  but  could  find  no  relation  between  them. 
He  found  a  very  low  number  of  leucocytes  in  a  case  in  which  the 

1  H.  Vogt.  Ein  Stoffwechselversuch  bei  akuter  Gicht.  Deutsche.  Arch,  fiir  klin. 
Medizin,  71,  21   (1901). 

-  Tereg  und  Lehmann.  Das  Verhalten  der  Calcium  Phosphate  im  Organismus  der 
Fleischfrcsser.     Pfliiger's  Archiv,   32,   122   (1883). 

Schetehg.  Ueber  der  Herstammung  und  Ausscheidung  des  Kalkes  im  Gesunden  und 
kranken  Organismus.     Virchow's   Archiv,   82,   437. 

E.  Lehmann.  Zur  Wirkung  des  kohlensauren  Kalkes  und  der  kohlensauren  Magnesia. 
Berl.  klin.  Woehenschrift,  21  (1882),  and  Zur  Wirkung  des  kohlensauren  Kalkes.  Berl.  klin. 
Wochenschrift,  31,  23   (1893). 

See,  also,  Goldthwait,  Painter,  and  Osgood.  The  preliminary  report  of  a  series  of 
Metabolism  Observations  made  in  Atrophic  Arthritis,  Hypertrophic  Arthritis,  Osteitis 
Deformans  and  the  Normal.     American  Medicine,  7,  547,  and  590  (1904). 

3  O.  Williamson.  On  the  Relation  Existing  between  Uric  Acid  Excretion  and  the  Break- 
ing Down  of  the  White  Blood  Corpuscles.     Lancet,  1903,  I,  1580. 

■*  Neusser.  Ueber  einen  besonderen  Blutbefund  bei  uratische  Diathese.  Wiener 
khn.  Wochenschrift,  7,  727  (1894). 

s  Bohland.  Ueber  den  Einfluss  einiger  Arzneimittel  auf  die  Bildung  und  Ausscheidung 
der   liarnsaure.     Miinchener   Mediz.   Wochenschrift,   46,   505   (1899). 

s  Girandeau.  Note  sur  un  cas  de  Leukooythemie  splenique.  Arch,  de  physiologie 
norm,  et  pathoL,  No.  8,  1884. 


Physiology  125 

uric  acid  had  increased  to  four  times  the  normal  amount.  After 
Horbaczewski's  work,  Matthes  ^  found  the  amount  of  uric  acid 
excreted  in  leukemia  normal,  and  Jacob  and  Kriiger  -  likewise 
found  no  parallelism  between  the  uric  acid  excretion  and  the 
leucocytosis  in  leukemia,  although  the  uric  acid  excretion  was 
somewhat  high.  Richter^  studied  the  leucocytosis  and  the  ex- 
cretion of  uric  acid,  not  only  in  leukemia,  but  in  a  number  of 
diseases,  and  found  no  relation  between  the  two.  He  remarked 
that  we  do  not  know  when  the  increased  cell  destruction  corre- 
sponding to  the  hyperleucocytosis  takes  place,  and  that  from  the 
amount  of  uric  acid  in  the  urine  we  cannot  tell  the  total  amount 
formed. 

It  was  in  1895  when  Horbaczewski's  theory  was  apparently 
confirmed  by  some  experimenters  and  contradicted  by  others, 
that  Kriiger  and  Wulff*  published  a  rather  simple  method  of 
determining  the  total  purin  bodies  of  the  urine.  Since,  outside 
the  body  the  purin  bases  are  obtained  as  decomposition  products 
of  nucleoproteid,  it  seemed  possible  that  there  might  be  some 
connection  between  decomposition  of  leucocytes  and  the  amount 
of  purm  bases  in  the  urine,  so  that  within  a  year  or  two  after  the 
publication  of  Kriiger  and  Wulff's  method,  a  number  of  articles 
appeared  dealing  with  the  relation  between  leucocytosis  and  the 
purin  bases  in  the  urine. 

Among  the  first  articles  was  that  of  Bondzynski  and  Gottlieb,^ 
who  found  that  the  excretion  of  purin  bodies  as  a  wdiole,  that  is, 
the  bases,  xanthin,  hypoxanthin,  guanin,  and  adenin,  plus  uric 
acid,  is  parallel  with  the  leucocytosis.  These  authors  believed 
that  their  w^ork  explained  the  contradictory  results  obtained  by 
former  experimenters.  When  there  is  leucocytosis  and  normal 
uric  acid  excretion,  then  the  purin  bases  in  the  urine  are  high. 
When  the  uric  acid  is  high,  it  is  due  to  an  oxidation  of  these  purin 
bases.     They  found  in  their  cases  of  leukemia  normal  excretion 

1  Matthes.  Zur  Chemie  des  leukamischen  Blutes.  Berl.  klin.  Wochenschrift,  Vol. 
31,  pp.  531  and  556  (1894). 

2  P.  Jacob  und  M.  Kruger.  Ueber  Harnsaure,  Xanthinbasen,  und  Leukocyten  bei 
einem  mit  Organextrakten  behandelten  Falle  von  Leukamie.  Deutsche  med.  Wochen- 
schrift, Vol.  20,  pp.  641  and  663  (1894). 

3  P.  Richter.  Ueber  Harnsaureausscheidung  und  Leukocyten.  Zeitschr.  fiir  khn.  Med., 
27,  290  (1895). 

*  M.  Kruger  und  C.  Wulff.  Ueber  eine  Methode  zur  quantitativen  Bestimmiing  der 
sogenannten  Xanlhinkorper  der  liarne.     Zeitschr.  fiir  physiol.  Chem.,  20,  176  (1895). 

^  St.  Bondzynski  und  R.  Gottlieb.  Ueber  Xanthinkorper  im  Harne  eines  Leukamikers. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  36,  127  (1895). 


126    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

of  uric  acid,  but  increased  excretion  of  purin  bases.  Gumprecht  ^ 
confirmed  this  parallelism  of  the  excretion  of  purin  bases  and  the 
number  of  leucocytes  in  the  blood.  He,  too,  found  normal  uric 
acid  excretion,  but  increased  excretion  of  purin  bases  in  leu- 
kemia. Kolisch  and  StejskaP  and  Kolisch  and  DostaP  as  a 
result  of  their  work  believed  the  excretion  of  purin  bodies  a  direct 
expression  of  the  decomposition  of  the  leucocytes. 

Kiihnau,*  too,  found  that  the  excretion  of  purin  bases  varies 
with  the  number  of  leucocytes  in  the  blood,  and  was  confirmed 
by  Kiihnau  and  Weiss.''  Later,''  he  found  that  injection  of  blood 
into  an  animal  causes  an  increased  excretion  of  uric  acid,  propor- 
tional to  the  number  of  leucocytes  in  the  blood  injected,  and  ex- 
pressed the  view  that  the  excretion  of  purin  bodies  is  a  direct 
measure  of  the  leucocyte  decomposition.  Drabczyk,^  as  a  result 
of  work  which  he  did,  came  to  the  same  conclusion  as  Kiihnau. 

Unfortunately,  all  these  experimenters  used  the  method  of 
Kriiger  and  Wulff  in  their  determinations  of  the  purin  bodies  of 
the  urine.  Weintraud,*  Ziilzer,''  Laquer,^"  Huppert,"  and  Sal- 
kowski  ^^  have  shown  that  this  method  is  unreliable,  so  that  the 
conclusions  arrived  at  from  determination  of  the  purin  bodies  in 
the  urine  by  this  method  are  valueless.     Flatow  and  Reitzenstein  ^^ 

1  Gumprecht.  Alloxurkorper  und  I^eukocyten  beim  Leukamiker.  Centralblatt  fiir 
allgem.  Path,  und  path.  Anat.,  7,  820  (1S96). 

2  R.  KoUsch  und  K.  Stejskal.  Ueber  die  durch  Blutzerfall  bedingten  Veranderungen 
des  Harnes.     Zeitschr.  fiir  klin.  Med.,  27,  446  (1895). 

3  R.  Kohsch  und  H.  Dostal.  Das  Verhalten  der  Alloxurkorper  in  pathologischen 
Harnen.     Wiener   klin.    Wochenschrift,    8,    413    (1895). 

*  W.  Kiihnau.  Experimentelle  und  klinische  Untersuchungen  iiber  das  Verhaltniss 
der  Harnsaureausscheidung  zur  Leukocytose.     Zeitschr.  fiir  klin.  Med.,  28,  534  (1895). 

■'  W.  Kiihnau  und  F.  Weiss.  Weitere  Mitteilungen  zur  Kenntnis  der  Harnsaure  Aus- 
scheidung  bei  licukocytose  und  Hyperleukocytose  sowie  zur  Pathol ogie  der  Leukamie. 
Zeitschr.   fiir   khn.    Med.,    32,   482    (1897). 

*  W.  Kiihnau.  Ueber  das  Verhalten  des  Stoffwechsels  und  der  weissen  Blutelemente 
bei  Blutdissolution.     Deutsche  Arch,  ftir  klin.  Medizin,  58,  339  (1897). 

^  T.  Drabczyk.  Ueber  die  Methode  zur  Bestimmung  der  Harnsaure  und  ein  Beitrag 
zur  Theorie  der  Entstehung  der  Harnsaure.  Maly's  .Jahresb.  iiber  die  Fortschritte  der 
Thierchemie,  26,  353  (1896). 

s  Weintraud.     Beitrage  zur  Stoffwechsel  der  Gicht.     Charity  Annalen,   215   (1895). 

9  G.  Ziilzer.  Ueber  die  Alloxurkorperausscheidung  ira  Harne  bei  Nephritis.  Berl. 
Win.   Wochenschrift,   23,  72   (1896). 

1"  B.  Laquer.  Ueber  die  Kriiger- Wulffsche  Methode  der  Alloxurkorperbestimmung 
Centralblatt   fur  innere-Medizin,    17,    1129    (1896). 

^1  H.  Huppert.  Ueber  die  Bestimmung  der  Xanthinbasen  nach  Kriiger-Wulff.  Zeit- 
schr.  fiir  physiol.   Chem.,   22,   556   (1897). 

'2  E.  Salkowski.  Ueber  die  Kriiger-Wulffsche  Methode  zur  Bestimmung  der  Allox- 
urkorper ini  Harne.     Deutsche  med.  Wochenschrift  23,  213  (1897). 

13  R.  Flatow  und  A.  Reitzenstein.  Zur  Xanthinbasenbestimmung  im  Urin.  Deutsche 
med.  Wochenschrift,  23,  354  (1897). 


Physiology  127 

showed  that  the  \Yulff-Kruger  method  gives  much  higher  results 
than  the  Salkowski  method,  in  fact,  as  much  as  seven  times  higher 
in  some  cases. 

During  the  last  few  years  a  number  of  men  have  studied  the 
relation  of  the  excretion  of  uric  acid  to  the  number  of  leucocytes 
in  the  blood,  and  have  found  no  relation  between  the  two.  Matthes  ^ 
and  Miinzer  ^  have  studied  the  excretion  of  uric  acid  in  leukemia 
and  found  it  normal.  Neither  Pope,^  Wey,*  nor  Stroux  and 
Levison^  could  find  any  coincidence  of  hyperleucocytosis  and 
high  excretion  of  uric  acid. 

Zagari  and  Pace  ^  studied  carefully  the  relation  of  the  number 
of  leucocytes  to  the  excretion  of  uric  acid,  and  found  that  in  leu- 
kemia the  increase  in  the  number  of  leucocytes  and  the  increase 
in  uric  acid  excretion  are  not  parallel.  They  found,  too,  that 
while  the  increased  excretion  of  uric  acid  after  eating  meat  is 
much  higher  than  after  a  vegetable  diet,  the  number  of  leucocytes 
is  not  dependent  on  whether  the  food  is  animal  or  vegetable. 
They  found  further  that  spermin  increases  the  excretion  of  purin 
bases  and  uric  acid,  but  does  not  change  the  number  of  leucocytes. 

Mayer  ^  found  that  although  the  ingestion  of  thymus  gland  in- 
creases the  excretion  of  uric  acid,  it  does  not  increase  the  number 
of  leucocytes.  He  found,  also,  cases  where  there  is  a  low  uric 
acid  excretion  and  a  high  number  of  leucocytes.  Camerer^  found 
that  while  thymus  does  cause  a  slight  increase  in  the  number  of 
leucocytes,  this  increase  is  not  greater  than  the  increase  caused 
by  ingestion  of  the  same  quantity  of  milk.  The  thymus  brings 
about  an  increased  excretion  of  uric  acid,  but  the  milk  does  not. 
Spleen  nuclein  was  found  by  Jakob  and   BergelP  to  cause  in- 

1  M.  Matthes.  Zur  Chende  cles  leukamischen  Blutes.  Berl.  klin.  Wochenschrift,  31,  531 
(1894). 

2  E.  Miinzer.  Die  Bedeutung  der  Ammoniaksalze  fur  die  Pathologie,  nebst  einen 
Beitrage  zura  Stoffwechsel  der  Leukamie.     Prager  Mediz.  Wochenschrift,  22,  171  (1897). 

3  C.  Pope.  Zur  Kenntnis  der  Beziehungen  zwischen  Hyperleucocytose  und  AUoxur- 
korperausscheidung.     Centralblatt  fiir  innere  Medizin,   20,  657   (1899). 

*  Way.     Beitrage  zur  Kenntnis  der  Leukamie.     Archiv.  fiir  klin.  Med.,  57,  287  (1896). 

5  Stroux  und  Le^'ison.     Dissert.,  Bonn.,   1897. 

6  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  alia  indirizzo  terapeutico.  Napoli,  1897,  from  Centralblatt  fiir  innere  Medizin, 
19,  816  (1898). 

''  P.  Mayer.  Leber  den  Einfluss  von  Nuklein  und  Thyreoidinfutterung  auf  die  Harn- 
saureausscheidung.     Deutsche  med.  Wochenschrift,  22,  186  (1896). 

8  W.  Camerer.  Harnsaure,  Xanthinbasen,  und  Phosphorsaure  im  menschlichen  Urin. 
Zeitschr.  fur  Biol.,  33,  139  (1898). 

**  P.  Jakob  und  P.  Bergell.  LTeber  den  Einfluss  nukleinhaltiger  Nahrung  auf  Blut  und 
Stoffwechsel  unter  besonderer  Beriichtsichtigung  den  Phosphorsaurestoffwechsels.  Zeitschr. 
fur  klin.  Med.,  35,  171  (1898) 


128    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

creased  excretion  of  uric  acid.  There  was,  however,  no  parallel 
increase  of  the  number  of  leucocytes. 

Fahraens  ^  found  that  in  starving  persons  there  is  as  much 
variation  in  the  number  of  leucocytes  during  the  day  as  in  a 
person  who  has  food  and  has,  therefore,  the  so-called  digestive 
leucocytosis.  Yet  in  starving  persons  the  uric  acid  excretion  is 
constant.^  This  would  seem  to  indicate  that  there  is  no  depend- 
ence of  the  uric  acid  excretion  upon  the  number  of  leucocytes. 
Siven^  found  different  quantities  of  leucocytes  in  the  blood  on 
different  days,  although  the  food  was  the  same.  He  found,  like- 
wise, almost  a  constant  quantity  of  uric  acid  excreted  with  a 
variable  number  of  leucocytes. 

Kriiger  and  Schmidt^  found  that  hypoxanthin  increases  the 
excretion  of  uric  acid  but  does  not  increase  the  number  of  leuco- 
cytes in  the  blood.  Croton  oil,  which,  according  to  Weiss ,^  gives 
a  hyperleucocytosis,  does  not  give  an  increased  excretion  of  uric 
acid.^  Further,  Magnus-Levy**  studied  the  excretion  of  purin 
bodies  and  uric  acid  in  leukemia  and  found  no  increase  in  the 
excretion  of  either,  and  Loewi^  found  no  change  in  the  relative 
amounts  of  different  nitrogenous  urinary  constituents  in  leukemic 
urine.  Henderson  and  Edwards  ^  found  the  excretion  of  uric  acid 
even  rather  low  in  leukemia.  Melis-Schirru^  found  quite  fre- 
quently an  increased  excretion  of  uric  acid  without  a  hyperleuco- 
cytosis. 

Another  objection  that  has  been  raised  against  Horbaczewski's 
theory  is    that    the   increase  in    the  number  of   leucocytes  in  a 

1  Bruhn  F&,hraens.  Klinische  Studien  iiber  die  Zahl  der  weissen  Zellen  im  menschlichen 
Blute.     Nod.  med.  Ark.,  1897,  p.  46. 

2  Schreiber  und  Waldvogel.  Beitrag  zur  Kenntnis  der  Harnsaureausseheidung  unter 
physiologischen  und  pathologischen  Verhaltnissen.  Arch,  ftir  exp.  Path.  u.  Pharmak.,  42, 
69  (1899). 

3  V.  Siven.  Zur  Kenntnis  der  Harnsaurebildung  im  inenschUchen  Organisnius  unter 
physiologischen  Verhaltnissen.     Skandinav.  Archiv.  f.  Physiologie,   11,  123  (1901). 

^  Kriiger  und  Schmidt.  Die  Entstehung  der  Harnsaure  ,aus  freien  Purinbasen.  Zeitschr. 
fur  physiol.  Chem.,  34,  549  (1901-1902). 

^  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fur  physiol.  Chem.,  27,  216  (1899). 

6  A.  Magnus-Levy.  Ueber  den  Stoflwechsel  bei  akuter  und  chronischen  Leukamie. 
Virchow's    Archiv,    152,    107    (1898). 

"  O.  Loewi.  Beitrage  zur  Kenntnis  des  Nukleinstoffwechsels.  1  Mitheil.  Archiv.  fiir 
exp.  path.  u.  Pharmak.,  44,  1  (1900). 

8  Y.  Henderson  and  G.  Edwards.  A  Study  of  Metabolism  in  a  Case  of  Lymphatic 
Leukemia.  Am.  Journ.  of  Physiol.,  6,  xxii,  1902,  and  Nuclein  Metabolism  in  Lymphatic 
Leukemia.     Am.  Journ.   of  Physiol.,  9,  417   (1903). 

s  Melis  Schirru.  Sulla  genesi  dell'  acido  urico.  Centralblatt  fiir  innere  Medizin,  20, 
1042    (1899). 


Physiology  129 

peripheral  vessel,  which  was  used  as  a  measure  of  the  number  of 
leucocytes  in  the  blood,  does  not  necessarily  indicate  increased 
leucolysis,  or  even  a  general  increase  in  the  number  of  leucocytes 
throughout  the  blood.  Rieder  ^  was  the  first  to  call  attention  to 
the  fact  that  an  increase  in  the  number  of  leucocytes  in  a  periph- 
eral vessel  does  not  necessarily  indicate  increased  leucolysis. 
Indeed,  he  and,  later,  his  pupil  Schulz  ^  found  that  when  the 
number  of  leucocytes  in  the  peripheral  vessels  increases,  there  is 
a  corresponding  decrease  in  the  number  of  leucocytes  in  the 
internal  vessels,  and  that  when  there  is  a  peripheral  hypoleu- 
cocytosis,  there  is  an  increase  in  the  number  of  leucocytes  in 
internal  vessels.  They  came  to  the  conclusion  that  the  total 
number  of  leucocytes  in  the  body  is  nearly  constant. 

Goldscheider  and  Jacob  ^  obtained  results  somewhat  similar 
to  those  of  Rieder  and  Schulz.  These  authors,  too,  showed  that 
a  decrease  in  the  number  of  leucocytes  in  a  peripheral  vessel  does 
not  necessarily  indicate  a  leucolysis,  but  find  that  in  this  case  the 
capillaries  of  the  lungs  are  well  filled  with  leucocytes.  They  do 
not,  however,  conclude  that  the  total  number  of  leucocytes  is 
constant.  Richter  and  Spiro*  and  Bohland^  from  experimental 
evidence  came  to  the  same  conclusion  as  Goldscheider  and  Jacob. 

In  explanation  of  the  fact  that  sometimes  a  large  increase  in 
the  number  of  leucocytes  was  often  accompanied  by  only  a 
small  increase  in  the  excretion  of  uric  acid,  and  that  a  considerable 
increase  in  the  excretion  of  uric  acid  was  often  accompanied  in 
his  experiments  by  only  a  slight  increase  in  the  number  of  leu- 
cocytes, Horbaczewski  said  that  the  quantity  of  the  nuclei  sub- 
stance in  different  individual  leucocytes  is  different,  and  that, 
consequently,  a  hyperleucocytosis  of  leucocytes  poor  in  nucleo- 
proteid  would  not  give  the  same  amount  of  uric  acid  on  decom- 
position as  a  hyperleucocytosis  of  leucocytes  rich  in  nuclear  sub- 
stance.    Mares'^  pointed  out  that  this  explanation  in  itself  was 

1  H.  Rieder.  Beitrage  zur  Kenntnis  der  Leukocytose  und  verwandter  Zustande  des 
Blutes,  203.     Leipzig,  1892. 

•  Schulz.  Experiment elle  Untersuchungen  iiber  das  Vorkommen  und  die  diagnostische 
Bedeutung  der  Leukocytose.     Arch,  fiir  khn.  Med.  51,  234,  1893. 

3  Goldscheider  und  Jacob.  Ueber  die  Variationen  der  Leukocytose.  Zeitschr.  fur 
klin.  Med.,  25,  373  (1894). 

■*  Richter  und  Spiro.  LTeber  die  Wirkung  intravenoser  Ziramtsaureinjectionen  auf  das 
Blut.     Archiv.  fiir  exp.  Path.  u.  Pharmak.,  34,  289  (1894). 

5  Bohland.  Ueber  die  Einwirkung  den  Hidrotica  und  Antihidrotica  auf  den  Leukocy- 
tengehalt  des  Blutes.     Centralblatt  fiir  innere  Medizin,  20,  361  (1899). 

6  F.  Mares.  Zur  Theorie  der  Harnsaurebildung  im  Saugethierorganismus.  Monat- 
shefte  fiir  Chemie,  13,  101  (1892). 


130   The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

an  objection  to  the  theory,  since  Horbaczewski  counted  only  the 
number  of  leucocytes  in  his  experiments  and  did  not  indicate 
the  amount  of  nuclear  substance.  Another  objection  that  Mares 
brought  up  in  the  same  article  is  that  if  the  leucocytes  are  the 
source  of  uric  acid,  then  those  of  the  spleen,  lymph,  and  intersti^ 
tial  tissue  must  have  a  very  great  influence  on  the  excretion  of 
uric  acid.  Horbaczewski  evidently  believed  that  the  number  of 
leucocytes  in  the  blood  alone  serves  as  a  measure  of  the  uric  acid 
excretion. 

Weintraud  ^  found  that  nuclein  which,  when  taken  in  the  food 
serves  to  increase  the  excretion  of  uric  acid,  does  not  always  in- 
crease the  number  of  leucocytes.  In  this  respect  he  found  that 
meat  gives  a  greater  hyperleucocytosis  than  nuclein,  although 
it  does  not  increase  the  excretion  of  uric  acid  so  much.  He 
summed  the  matter  up  saying  that  so  long  as  we  judge  the  uric  acid 
formation  by  the  uric  acid  excretion  and  the  leucocyte  decompo- 
sition by  the  number  of  leucocytes  in  a  peripheral  vessel,  so  long 
will  we  try  in  vain  to  prove  Horbaczewski 's  hypothesis  that  the 
formation  of  uric  acid  is  due  to  the  decomposition  of  leucocytes. 
In  regard  to  the  first  part  of  his  statement,  we  now  believe  that 
there  is  a  relation  between  the  uric  acid  formation  and  the  uric 
acid  excretion. 

The  uric  acid  excreted  cannot  all  come  from  the  food,  for 
Tuczek^  showed  long  ago  that  it  does  not  disappear  from  the 
urine  in  starvation.  In  this  he  has  been  confirmed  by  many 
experimenters.  Then,  since  nucleoproteid  can  serve  as  a  source 
for  uric  acid,  and  since  the  leucocytes  are  rich  in  nucleoproteid,  it 
seems  a  priori  probable  that  some  of  the  uric  acid  excreted  is 
derived  from  them.  This,  too,  is  the  conclusion  that  Zagari  and 
Pace^  and  Douglas*  come  to.  The  experimental  results  of 
Douglas  in  some  respects  contradict  those  of  Zagari  and  Pace, 
but  they  both  conclude  that  while  the  number  of  leucocytes  may 
have  some  effect  on  the  excretion  of  uric  acid,  yet  this  effect  has 
been  greatly  overrated. 

1  W.  Weintraud.  Ueber  den  Einfluss  des  Nukleins  der  Nahrung  auf  die  Harnsaure- 
bildung.     Berl.  klin.  Wochenschrift,  32,  405  (1895). 

^  I'.  Tuczek.  Mittheilung  von  Stofifwechseluntersuchungen  bei  abstinirenden  Geis- 
teskranken.     Archiv.    fiir   Psychiatrie,    15,    784    (1884). 

3  G.  Zagari  e  D.  Pace.  La  genesi  dell'  aeido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  alia  indirizzo  terapeutico.  Napoli,  1897.  From  Centralblatt  fiir  innere  Medizin, 
19,  816  (1898). 

■*  C.  Douglas.  Some  Observations  on  the  Excretion  of  Uric  Acid  with  Special  Reference 
to  Its  Connection  with  Leucocytosis.     Edinburgh  Med.  Journ.,  1900,  p.  32. 


Physiology  131 

Uric  Acid  from  Cells  other  than  the  Leucocytes. — As  Jakob  ^ 
pointed  out,  there  are  nucleoproteids  in  the  nuclei  of  cells 
other  than  the  leucocytes  that  may  serve  as  a  source  for  uric 
acid.  He  believed  that  the  increased  excretion  of  uric  acid 
in  the  degeneration  of  the  liver  caused  by  phosphorous  poisoning 
comes  from  the  nucleoproteid  of  the  nuclei  of  the  liver  cells. 
This  increased  excretion  of  uric  acid  in  phosphorous  poisoning 
had  been  previously  noted  by  Horbaczewski,^  Miinzer,^  and 
Lieblein.^  Nencki,  Pawlow,  and  Zaleski^  also  noticed  increased 
excretion  of  uric  acid  in  liver  degeneration,  and  gave  it  the  same 
explanation  that  Jakob  did.  It  may  be  noted  that  von  Jaksch  * 
has  found  an  increase  in  the  excretion  of  ammonia,  urea,  and 
amino-nitrogen,  as  well  as  uric  acid  in  phosphorous  poisoning. 

Another  view  of  the  source  of  the  uric  acid  from  the  body 
tissue  is  that  of  Minkowski,^  that  it  may  be  as  well  due  to  an  in- 
creased function  of  the  cell  as  an  increased  destruction.  This, 
too,  is  the  view  of  Melis-Schirru,^  who  ascribes  both  hyperleuco- 
cytosis  and  increased  excretion  of  uric  acid  to  a  common  cause. 
Melis-Schirru  noticed  quite  frequently  an  increased  excretion  of 
uric  acid  without  a  coincident  hyperleucocytosis,  but  never  a 
hyperleucocytosis  without  an  increase  in  the  uric  acid  excretion. 
He  thinks  that  an  increased  function  of  the  lymph  organs  leads  to 
a  storing  up  of  nuclein  substance  in  them,  and  this  leads  first  to  an 
increased  excretion  of  uric  acid  and  later  to  a  hyperleucocytosis. 
The  view  that  increased  excretion  of  uric  acid  is  connected  with 
increased  function  of  cells  is  likewise  that  of  Mares ,^  who  thinks 

1  p.  Jakob.  Ueber  Harnsaure,  Xanthinbasen,  und  Leucocytose  bei  Leukamie.  Vortr. 
geh.  in  d.  physiol.  Gesell.  zu  Berlin  am  13  April,  1894.     Du  Bois  Archiv,  378  (1894). 

2  Horbaczewski.  Beitrage  zur  Kenntnis  der  Bildung  der  Harnsaure  und  der  Xanthin- 
basen sowie  der  Entstehung  der  Leukocytose  im  Saugethierorganismus.  Monatshefte  fiir 
Chemie,  12,  221  (1891). 

3  E.  Miinzer.  Der  Stoffwechsel  des  Menschen  bei  akuter  Phosphorvergiftung.  Deutsch. 
Arch.  fiir.  klin.  Med.,  52,  199  (1894). 

*  V.  Lieblein.  Die  Stiokstoffausscheidung  nach  Leberverodung  beim  Saugethiere. 
Archiv.  fiir  exp.  Path.  u.  Pharmak.,  33,  318  (1894). 

5  Nencki,  Pawlow,  und  Zaleski.  Ueber  den  Ammoniakgehalt  des  Blutes  und  der 
Organe  und  die  Harnstoffbildung  bei  den  Saugethieren.  Arch,  fiir  exp.  Path.  u.  Pharmak., 
37,  26  (1896). 

^  R.  V.  Jaksch.  Ueber  die  Verteilung  des  Stickstoffes  im  Harne  bei  einem  FaUe  von 
Phosphorvergiftimg  nebst  vergleichenden  Beobachtungen  liber  einige  neuere  Methoden  der 
Harnstoffbestimmung.     Zeitschr.  fiir  physiol.  Chem.,  40,  123  (1903). 

'  O.  Minkowski.  Ueber  Leukamie  und  Leucocytose.  Verhaudl.  des  17  Kongr.  fiir 
innere  Med.,  158  (1899). 

8  Melis-Schirru.  Sulla  genesi  dell'  acido  urioo.  Centralblatt  fiir  innere  Med.,  20,  1042 
(1899). 

5  F.  Mares.  Sur  I'origine  de  I'acide  urique  chez  I'homme.  Axcliives  slaves  de  Biologic, 
3,  207  (1888).     Centralb.  fiir  med.  Wissen.,  26,  2  (1888). 


132    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

that  increased  excretion  of  uric  acid  is  brought  about  by  increased 
activity  of  the  digestive  glands.  He  pointed  out  that  the  excre- 
tion of  uric  acid  is  constant  in  starvation,  and  that,  after  a  pro- 
teid  diet,  the  increased  excretion  begins  within  an  hour  and 
attains  its  maximum  in  from  six  to  eight  hours.  Kam  ^  has  con- 
firmed this  latter  fact.  The  uric  acid  excretion,  therefore,  is 
parallel  with  the  activity  of  the  digestive  glands.  Further,  pilo- 
carpin,  which  increases  the  activity  of  all  glands,  increases  the 
excretion  of  uric  acid. 

From  Muscular  Activity.  —  Siven  ^  thinks  that  muscular  work 
may  cause  the  formation  of  that  part  of  the  uric  acid  which  is 
not  derived  from  the  food.  He  observed  an  increased  excre- 
tion of  uric  acid  after  muscular  exercise.  A  slightly  increased 
excretion  of  uric  acid  after  bodily  movement  had  been  noted 
by  Montessier,^  and  also  by  Herter  and  Smith.*  An  increased 
excretion  of  uric  acid,  to  the  extent  of  from  25  to  40  per 
cent,  had  been  noticed  by  Kolisch^  after  a  snow-shoe  party. 
Robin®  found  that  although  the  nitrogenous  metabolism  as  a 
whole  increased  during  the  muscular  exercise  in  bicycling,  the 
excretibn  of  uric  acid  decreased.  Laquer^  and  Zagari  ^  found 
decreased  excretion  of  uric  acid  during  muscular  work.  Blake 
and  Larrabee  ^  found  that  the  excretion  of  uric  acid  was 
decreased  in  the  runners  after  the  twenty-five  mile  Marathon 
race  at  Boston  to  a  slight  extent.  They  do  not,  however, 
give  their  figures  or  their   method  of   determination.     Accord- 

1  B.  Kara.  Bijdragen  tot  de  kennis  der  urinezuuruitscheidung.  Diss.  Leiden  (1898). 
Maly's  Jahresb.  uber  die  Fortschritte  der  Thierchem,  28,  573  (1898). 

■^  V.  Siven.  Zur  Kenntniss  der  Harnsaurebildung  im  menschlichen  Organismus  unter 
physiologischen  und  pathologischen  Verlialtnissen.  Skandinav.  Arohiv.  f.  Physiol.,  11, 
123   (1901). 

3  Montessier.  Wien.  medic.  Bl.,  1890,  No.  32.  Maly's  Jahresb.  uber  die  Fortschritte 
der  Thierchemie,  21,  182  (1892). 

*  C.  Herter  and  E.  Smith.  Observations  on  the  Excretion  of  Uric  Acid  in  Health  and 
in  Disease.     N.  Y.  Med.  .Journ.,  1892,  June  4,  p.  38. 

5  Kolisch  (from  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  AUoxurkorper  im 
Ham  von  Gesunden  und  Kranken.  Verhandl.  des  14  Kongr.  fi'ir  innere  Medizin,  Wies- 
baden, 333  L1S93]). 

8  A.  Robin.  Action  de  I'exercise  moderne  a  bicyclette  sur  I'acide  urique  et  clans  un  cas 
d'albuminurie  par  sclerose  renale  concomitante.  Centralblatt  fiir  innere  Med.,  359 
(1895). 

''  Laquer.  Ausscheidungsverhaltnisse  der  AUoxurkorper  im  Harn  von  Gesunden  und 
Kranken.     Verhandl.  des  14  Kongr.  fur  innere  Medizin,  Wiesbaden  (1896),  333. 

8  G.  Zagari.  Influenza  della  inalazioni  ossigeno  e  del  moto  sull'  eUminazione  dell'  acido 
urieo  e  corpi  affini.     Napoli  (1898). 

8  J.  Blake  and  R.  Larrabee.  Observations  upon  Long-Distance  Runners.  Boston 
Medical  and  Surgical  Journal.  Vol.  158,  No.  8,  195  (1903). 


Physiology  133 

ing  to  Sherman/  muscular  exercise  has  no  effect  on  the 
excretion  of  uric  acid  when  the  subject  experimented  on  is  in 
training.  Neither  LavaP  nor  Rockwood^  could  find  any  effect 
of  muscular  work  on  the  excretion  of  uric  acid.  According  to 
the  latter,  exhaustive  labor  causes  an  increase  in  the  excretion 
of  uric  acid. 

The  experiments  of  Genth  and  Henle/  who  found  that  exer- 
cise increases  the  excretion  of  uric  acid,  those  of  Hammond,^ 
who  found  the  excretion  decreased,  those  of  Lehmann,^  who 
found  it  unchanged,  and  those  of  Speck,''  who  found  it  some- 
times increased  and  sometimes  unchanged  by  exercise,  are  of  no 
value,  for  these  authors  used  the  inaccurate  Heinz  method  for 
determining  uric  acid.  As  a  result  of  a  few  experiments,  Dunlop, 
Paton,  Stockman,  and  Maccadam^  have  concuded  that  the  ex- 
cretion of  uric  acid  is  increased  except  when  the  patient  is 
in  training.  The  scanty  data  does  not  warrant  their  conclusion, 
however. 

Burian  ^  has  studied  the  effect  of  muscular  activity  on  the 
excretion  of  uric  acid  with  more  care  than  any  other  experimenters. 
This  author  found  that  although  on  days  of  muscular  activity 
there  is  no  greater  excretion  of  uric  acid  than  on  days  of  rest,  yet 
the  excretion  of  uric  acid  after  a  few  hours  of  muscular  exercise 
is  very  much  greater  than  after  a  similar  period  of  rest.  On 
further  study  of  the  subject,  Burian  found  that  if  diluted  defibrin- 
ated  blood  is  passed  through  an  isolated  muscle,  purin  bases  and 
uric  acid  are  found  in  the  blood  on  its  exit  from  tiie  muscle. 
When  the  muscle  was  stimulated  to  action  by  the  electric  current, 
more  hypoxanthin  and  uric  acid  was  found  in  the  blood  passing 

1  H.  Sherman.  On  the  Influence  of  Diet,  Muscular  Exertion,  and  Loss  of  Sleep  upon  the 
Formation  of  Uric  Acid  in  Man.     Journ.  Am.  Chem.  Soc,  25,  1158  (1903). 

2  E.  Laval.  De  I'influenee  des  exercises  physiques  sur  I'excretion  de  I'aeide  urique. 
Eevue  de  Mc^d.,  16,  384  (1896). 

s  E.  Rockwood.  The  Elimination  of  Endogenous  Uric  Acid.  Am.  Journ.  of  Physiol. 
12,  38  (1904). 

*  Henle.     Handbuch  der  rationelle  Pathologie,  I,  335. 

5  Hammond.  Am.  Journ.,  Jan.,  1855  (cited  by  Meissner.  Zeitsch.  fiir  rationelle  med., 
31,  234,  [1868]). 

8  Lehmann.     Arch,  fur  wissenschaftliche.     Heilkunde  4,  484. 

7  Speck.     Arch,  fur  wissenschaftliche.     Heilkunde  4,  521,  and  6,  161. 

8  J.  Dunlop,  D.  Paton,  R.  Stockman,  and  I.  Maccadam.  On  the  Influence  of  Muscular 
Exercise,  Sweating,  and  Massage  on  the  Metabolism.     Journ.  of  Physiol.,  22,  68  (1897). 

"  R.  Burian.  Die  Bildung  der  Harnsaure  im  Organismus  des  Menschen.  Med.  KUnik, 
1,   131   (1905). 

Ibid.  Die  Herkunft  der  endogenen  Harnpurine  bei  Mensch  und  Siiugethier.  Zeitschr. 
fiir  physiol.  Chem.,  43,  532  (1905). 


134   The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

out  of  the  muscle  than  when  the  muscle  was  at  rest,  and,  further, 
the  quantity  of  hypoxanthin  in  the  muscle  itself  increased.  As 
we  shall  see  later,  a  very  large  part  of  the  hypoxanthin  introduced 
into  the  body  is  excreted  as  uric  acid,  so  that  Burian's  results 
would  indicate  muscular  activity  as  a  source  of  uric  acid.  In 
fact,  this  author  believes  that  hypoxanthin  is  constantly  being 
formed  as  a  result  of  muscular  activity,  and  that  this  is  the  most 
important  source  of  the  endogenous  uric  acid  excreted.  This 
may,  to  some  extent,  explain  the  results  of  Rockwood,^  who  found 
the  hourly  excretion  of  uric  acid  greater  during  the  day  than 
during  the  night. 

In  regard,  then,  to  the  source  of  the  uric  acid  which  comes  from 
the  body  tissue,  we  cannot  at  this  writing  give  a  complete  state- 
ment. Burian's  work  seems  to  indicate  hypoxanthin  formed  in 
muscular  activity  as  one  source.  It  seems  probable  that  when 
cells  do  degenerate,  the  nucleoproteid  of  the  nuclei  can  serve  as  a 
source  for  uric  acid,  since  nucleoproteid  taken  in  the  food  is 
known  to  give  uric  acid,  so  that  in  leukemia,  and  after  the 
absorption  of  the  exudate  in  pneumonia,  and  also  after  the 
liver  degeneration  caused  by  phosphorous  poisoning,  we  la&j 
ascribe  a  cause  for  the  increased  excretion  of  uric  acid.  We 
have  no  proof  as  yet,  however,  that  the  physiological  varia- 
tions in  the  excretion  of  uric  acid  are  due  to  the  same  cause. 
We  can  say  nothing  positive  concerning  increased  cell  activity 
as  a  source  of  uric  acid.  There  is  no  definite  evidence  to 
show  that  this  is  the  case.  The  view  first  proposed  by  Weintraud 
that  uric  acid  in  the  urine  is  due  in  part  to  absorption  and 
oxidation  of  purin  bodies  from  the  mucous  membrane  of  the 
alimentary  canal  will  be  discussed  in  the  section  on  the  purin 
bodies  of  the  feces.  The  relative  importance  of  the  uric  acid 
derived  from  the  body  cells  and  that  derived  from  the  food  will 
be  discussed  later. 

The  Nucleins  and  Purin  Bodies  of  the  Food  as  a  Source 
OF  THE  Uric  Acid  and  Purin  Bodies  Excreted.  —  It  has 
been  seen  that  there  is  no  parallelism  between  the  concentration 
of  the  leucocytes  in  the  blood  and  the  amount  of  uric  acid 
excreted.     We  have  no  reason,  therefore,   to  believe  that  the 

1  E.  Rockwood.  The  Elimination  of  Endogenous  Uric  Acid.  Am.  Journ.  of  Physiol., 
12,  38  (1904). 


Physiology  135 

increased  excretion  of  uric  acid  after  feeding  bodies  containing 
nucleins  is  due  primarily  to  an  increased  decomposition  of 
leucocytes. 

We  now  have  abundant  evidence  to  show  that  food  con- 
taining nucleoproteids  increases  the  excretion  of  uric  acid. 
Only  Gumlich^  in  recent  times  missed  an  increased  excretion 
of  uric  acid  after  feeding  thymus  gland,  and  Mayer  ^  after 
feeding  spleen.  Gumlich  used  dogs  in  his  experiments.  We 
shall  see  later  that  in  dogs  uric  acid  is  oxidized  in^  part  to 
allantoin.  Further,  Gumlich  used  the  inaccurate  Heinz  method 
for  the  determination  of  uric  acid.  This  author  obtained  a 
slight  increase  in  the  extractive  matter,  which  may  be  due  to 
allantoin. 

Calves'  thymus  was  shown  by  Luethje^  and  Minkowski*  to 
increase  the  excretion  of  uric  acid  in  dogs.  Mayer  ^  and  Minkow- 
ski obtained  in  men  an  increased  excretion  of  uric  acid  after 
administration  of  100  grams  thymus.  Rosenfeld  and  Orgler^ 
replaced  500  grams  meat  by  thymus  in  the  diet  and  obtained  a 
large  increase  in  the  excretion  of  uric  acid.  Weiss  ^  found  the 
uric  acid  excretion  increased  after  replacing  375  grams  meat  by 
375  grams  thymus,  and  Weintraud  ^  after  administration  of  from 
750  to  1,000  grams  of  calves'  thymus  obtained  an  increased  ex- 
cretion of  uric  acid  for  two  days.  Hess  and  SchmolP  gave  a 
pretty  illustration  of  the  action  of  thymus.  They  showed  that 
if  a  certain  weight  of  yolk  of  egg  be  added  to  a  standard  diet, 
there  is  no  increase  in  the  excretion  of  uric  acid.  If,  instead  of 
yolk  of  egg,  the  same  weight  of  thymus  gland  is  used,  an  increase 
in  the  amount  of  uric  acid  excreted  is  noted. 

1  G.  Gumlich.  Ueber  die  Aufnahme  der  Nukleia  in  den  thierischen  Organismus.  Zeit- 
schr.  far  physiol.  Chem.,  18,  508  (1894). 

'  P.  Mayer.  Ueber  den  Einfluss  von  Nuklein-  und  Thyreoidin-fiitterung  auf  die  Harn- 
saureausscheidung.     Deutsche  med.  Wochenschrift,  22,  186  (1896). 

3  Luethje.  Ueber  Bleigicht  und  den  Einfluss  der  BleiLntoxication  auf  die  Harnsaure- 
ausscheidung.     Zeitschr.  fiir  klin.  Med.,   29,  266   (1896). 

^  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologic  der  Harnsiiure  bei 
Saugethieren.     Arch,  fur  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

=  Rosenfeld  und  Orgler.  Zur  Behandlung  der  harnsauren  Diathese.  Centralblatt  fur 
innere  Medizin,   17,  42  (1896). 

^  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fur  physiol.  Chem.,  27,  216  (1899). 

'  W.  Weintraud.  Ueber  Harnsaure  im  Blute.  Wiener  klin.  Ptundschau,  No.  1 
(1896). 

*  N.  Hess  und  E.  Schmoll.  Ueber  die  Beziehungen  der  Eiweiss  und  Paranuklein- 
substanzen  der  Nahrung  zur  AUoxurkorperausscheidung  im  Harne.  Arch,  fiir  exp.  Path. 
.  Pharmak.,  37,  243  (1896). 


136    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Mochizuchi/  Brandeburg,^  Jerome,^  Pope/  Weintraud,^  Umber/ 
Camerer/  and  Taylor/  all -observed  an  increased  excretion  of 
uric  acid  after  thymus  feeding  in  health,  while  Schmoll/  in  a 
gouty  patient,  and  Zagari  and  Pace/"  in  patients  with  nephritis 
and  leukemia,  observed  the  same  result,  so  that  there  can  be  no 
doubt  that  thymus  nuclein  at  least  gives  an  increase  in  the  ex- 
cretion of  uric  acid. 

Increased  excretion  of  uric  acid  has  been  obtained  by  Hopkins 
and  Hope  "  after  administration  of  herring  sperm  and  swine  sperm, 
and  also  after  the  administration  of  free  spleen  nuclein  and  yeast 
nuclein,  by  Weiss ^^  and  Taylor^  after  replacing  meat  by  pan- 
creas, by  Jakob  and  Bergell  ^^  after  feeding  spleen  nuclein  to  a 
patient,  by  Umber  ®  after  administration  of  liver,  and  by  Min- 
kowski ^*  after  administration  of  salmon  sperm.  Jerome  ^^  ob- 
tained a  rise  of  25  per  cent  in  the  excretion  of  uric  acid  after 
using  4  grams  free  nuclein  obtained  from  yeast,  and  a  rise  of  75 
per  cent  after  using  10  grams  of  free  nuclein  from  spleen. 

1  J.  Mochizuchi.  Ueber  die  Resorption  von  Eiweisskorpern  von  der  Schleimhaut  des 
Dickdarmes  nach  Versuchen  mit  Thymusklystieren.  Arch,  ftir  Verdauungskrankheiten, 
7,  222  (1901). 

2  C.  Brandeburg.  Ueber  die  diagnostische  Bedeutung  der  Harnsaure  und  Xanthin- 
basen  im  Urin.-    Berl.  klin.  Wochenschrift,  33,  137  (1896). 

3  W.  Jerome.  The  Formation  of  Uric  Acid  in  Man,  and  the  Influence  of  the  Diet  on  Its 
Daily  Output.     Journ.  of  Physiol.,  22,  146  (1898). 

*  C.  Pope.  Zur  Kenntniss  der  Beziehungen  zwischen  Hyperleukocytose  und  Alloxur- 
korperausscheidung.     Centralblatt  fiir  innere  Medizin,  20,  657   (1899). 

'  W.  Weintraud.  Ueber  Harnsaurebildung  beim  Menschen.  Vortrag.  geh.  in.  d. 
physiol.  Ge-sellsch.  zum  Berlin  am  1  Marz,  1895.     Du  Bois  Archiv,  382  (1895). 

6  F.  Umber.  Ueber  den  Einfluss  nukleinhaltiger  Nahrung  auf  die  Harnsaurebildung. 
Zeitschr.  fur  kUn.  Med.,  29,   174  (1896). 

'W.  Camerer.  Harnsaure,  Xanthinbasen,  und  Phosphorsaure  im  mensohlichen  Urin. 
Zeitschr.  fiir  Biol.,  33,  139  (1896). 

8  A.  Taylor.  The  Influence  of  Various  Diets  upon  the  Elimination  of  Uric  Acid  and 
the  Purin  Bases.     Amer.  Journ.  of  Med.  Sciences,  118,  141  (1899). 

8  E.  Schmoll.  Stoffwechselversuch  an  einem  Gichtiker.  Zeitschr.  fiir  klin.  Med.,  29, 
610   (1896). 

10  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  alia  indirizzo  terapeutico.  Napoli,  1897,  from  Centralblatt  fur  innere  Medizin, 
19,  816  (1898). 

11  Hopkins  and  Hope.  On  the  Relation  of  Uric  Acid  Excretion  to  Diet.  Journ.  of 
Physiol.,  23,  271  (1898). 

12  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fiir  physiol.  Chem.,  27,  216  (1899). 

13  P.  Jakob  und  P.  Bergell.  Ueber  den  Einfluss  nukleinhaltiger  Nahrung  auf  Blut  und 
Stoffwechsel  unter  besonderer  Beriicksichtigung  des  Phosphorsaurestoffwechsels.  Zeitschr. 
fiir  klin.  Med.,  35,  171  (1898). 

"  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

15  W.  Jerome.  Further  Proofs  of  the  Origin  of  Uric  Acid  from  Nuclein  Compounds. 
Journ.  of  Physiol.  25,  98  (1898-99). 


Physiology  137 

Richter  ^  found  an  increased  excretion  of  uric  acid  for  two  days 
after  feeding  10  grams  of  the  sodium  salt  of  nucleic  acid,  and 
Minkowski  ^  obtained  the  same  result  in  dogs  and  in  men  after 
feeding  thymus  nucleic  acid  and  salmon  nucleic  acid.  All  these 
foodstuffs,  —  thymus,  fish  sperm,  yeast,  hver,  pancreas,  spleen,  and 
so  forth,  —  which  have  been  found  to  increase  the  excretion  of  uric 
acid,  are  rich  in  nucleoproteid,  and  therefore  in  purin  bases.  We 
shall  see  that  Burian  and  Schur  ^  were  able  to  show  quantitatively 
how  much  uric  acid  can  be  obtained  from  a  weighed  amount  of 
nuclein. 

Since  food  material  containing  nucleins,  the  free  nucleins 
themselves,  and  nucleic  acid  were  found  to  increase  the  excretion 
of  uric  acid,  since  this  increase  is  not  caused  by  an  intermediate 
decomposition  of  leucocytes,  and  since,  as  will  be  shown  later, 
foodstuffs  other  than  those  containing  purin  bases  do  not  influ- 
ence the  excretion  of  uric  acid,  it  seemed  certain  from  the  close 
chemical  relation  between  the  purin  bases  and  uric  acid  that 
increased  excretion  of  uric  acid  after  nuclein  feeding  is  due  to 
the  presence  of  these  bases,  yet  Nencki  and  Sieber^  and  Stadt- 
hagen^  who  fed  xanthin  to  dogs,  Kerner  "^  who  fed  guanin,  and 
Kossel  ^  who  fed  adenin  could  not  observe  an  increased  excretion 
of  uric  acid.  We  shall  see,  however,  that  dogs  do  not  react  ex- 
actly like  other  animals  toward  purin  bases.  Instead  of  increased 
excretion  of  uric  acid,  we  are  more  likely  to  get  an  increased 
excretion  of  allantoin,  an  oxidation  product  of  uric  acid.  Min- 
kowski^ was  the  first  to  obtain  increased  excretion  of  uric  acid 

'  p.  Richter.  Ueber  Harnsaureausscheidung  und  Leucocytose.  Zeitschr.  fiir  klin. 
Med.,  27,  290  (1895). 

2  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologic  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

3  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     I.  Mitteilung.     Pfliiger's  Archiv.,   80,   241    (1900). 

Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoffwechsel.  II.  Mitteilung. 
Pfliiger's  Archiv,  87,  239  (1901). 

Das  quantitative  Verhalten  der  menschlichen  Harnpurinausscheidung.  Pfliiger's  Archiv, 
94,  273  (1903). 

^  M.  Nencki  und  N.  Sieber.  Ueber  eine  neue  Methode,  die  physiologische  Oxydation 
zu  messen  und  iiber  den  Einfluss  der  Gifte  und  Krankheiten  auf  dieselbe.  Pfliiger's  Archiv, 
31,  319  (1883). 

s  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaure  in  verschiedenen  tierschen 
Organen,  ihr  Verhalten  bei  der  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  Stick- 
stoffbasen.     Virchow's  Archiv,  109,  390  (1887). 

6  Kerner.  Ueber  das  Verhalten  das  Guanins.  Annal.  d.  Chem.  und.  Pharm.,  103, 
249  (1857). 

7  A.  Kossel.     Ueber  das  Adenin.     Zeitschr.  fiir  physiol.  Chem.,  12,  241  (18SS). 

8  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir.  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 


138   The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

after  administration  of  free  purin  bases.  He  found  that  xanthin 
and  hypoxanthin,  but  not  adenin,  gives  increased  excretion  of 
uric  acid,  even  in  dogs.  Burian  and  Schur  ^  found  that  xanthin 
and  hypoxanthin  give  increased  excretion  of  uric  acid  in  men, 
and  Kriiger  and  Schmidt  ^  found  that  adenin,  and  to  a  slight 
extent  guanin,  give  increased  uric  acid  excretion. 

The  proof  that  the  free  purin  bases  increase  the  excretion  of 
uric  acid  is  very  important,  since  it  explains  the  relationship 
between  the  diet  and  the  uric  acid  in  the  urine/  A  number  of 
authors  had  maintained  that  the  amount  of  uric  acid  excreted 
is  dependent  upon  the  amount  of  proteid  in  the  food.  Others 
denied  any  relationship  between  the  two.  Practically  all  authors, 
however,  agreed  that  a  meat  diet  gives  more  uric  acid  than  a 
vegetable  diet. 

Only  Jones  ^  found  no  difference  in  the  amount  of  uric  acid 
excreted,  whether  the  diet  consisted  chiefly  of  meat  or  of  vege- 
tables ;  but  he  employed  the  useless  Heinz  method  for  the  deter- 
mination of  uric  acid.  Lehmann  ^  found  1.0  gram  uric  acid  ex- 
creted in  twenty-four  hours  on  a  purely  vegetable  diet,  1.1  grams 
on  a  mixed  diet,  and  1.4  on  a  diet  consisting  chiefly  of  meat. 
H.  Ranke  ^  found  .88  gram  uric  acid  on  a  meat  diet  and  only  .65 
gram  on  a  vegetable  diet.  Haughton  ®  found  three  times  as 
much  uric  acid  excreted  by  beef  eaters  as  by  vegetarians.  Hor- 
baczewski  ^  found  that  the  excretion  of  uric  acid  is  diminished 
when  part  of  the  meat  in  the  diet  is  replaced  by  sugar  or  fat. 
The  results  of  Hermann  ^  on  the  excretion  of  uric  acid  in  twenty- 
four  hours  on  different  kinds  of  diet  are  .046  to  .050  gram  uric 
acid  nitrogen  on  a  vegetable  diet,  .060  to  .075  gram  on  a  mixed 
diet,  and  .097  to    .104   gram  on  a  meat   diet.     Rosenfeld   and 

1  R.  Bvirian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     I.  Mitteilung.     Pfliiger's  Archiv,  80,  241   (1900). 

Ibid.     II.  Mitteilung.     Pfliiger's  Archiv,  87,  239  (1901). 

2  M.  Kriiger  und  J.  Schmidt.  Ueber  die  Entstehung  der  Harnsaure  aus  freien  Purin- 
basen.     Zeitschr.  fiir  physiol.  Chem.,  34,  549  (1902). 

3  Jones.     Philosophical  Transactions,  796  (1849), 

*  Lehmann.      Lehrb.  d.  physiol.  Chem.,  2d  ed.,  Vol.  I  (1853). 

'  H.  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidung  der  Harnsaure  bei 
Menschen.     Miinchen  (1858). 

^  S.  Haughton.  On  the  Natural  Constants  of  the  Healthy  Urine  of  Man.  The  Dublin 
Quarterly,  28,  1  (1859). 

'  J.  Horbaczewski  und  F.  Kanera.  Ueber  den  Einfluss  von  Glycerin,  Zucker,  und  Fett 
auf  die  Ausscheidung  der  Harnsaure.     Monatshefte  fiir  Chemie,  7,  105  (1886). 

8  A.  Hermann.  Ueber  die  Abhangigheit  der  Harnsaureausscheidung  von  Nahrungs- 
und  Genussmitteln  mit  Riicksicht  auf  die  Gicht.  Deutsche  Arch.  fiir.  klin.  Medizin,  43, 
273  (1888). 


Physiology  139 

Orgler  *  found  in  the  twenty-four  hours'  urine  .374  to  .587  gram 
uric  acid  during  starvation,  .576  to  1.005  grams  with  600  grams 
meat,  .756  to  .776  gram  with  800  grams  meat,  and  1.299  to  2.793 
grams  with  1,650  grams  of  meat.  Dapper^  tried  several  sets  of 
experiments  upon  himself  and  upon  his  laboratory  servant,  and 
in  all  cases  found  a  decreased  excretion  of  uric  acid  when  part  of  the 
meat  in  the  food  was  replaced  by  vegetables,  fats,  or  carbohydrates. 
J.  Ranke,^  Bunge,^  Marez,^  Schultz,^  Schreiber  and  Waldvogel,^ 
Taylor,^  and  Burian  and  Schur  ^  likewise  found  that  higher  excre- 
tion of  uric  acid  is  brought  about  by  a  meat  diet  than  by  a  diet  of 
vegetables,  fats,  or  carbohydrates,  and  that  the  amount  of  uric 
acid  excreted  does  not  bear  a  constant  ratio  to  the  amount  of  urea. 
Milk,  in  this  respect,  acts  like  vegetable  food,  and  when  sub- 
stituted for  meat  brings  about  a  decrease  in  the  excretion  of  uric 
acid.  To  be  sure,  Kussmanoff  ^°  did  not  find  this  to  be  the  case, 
but  his  work  is  open  to  criticism.  Markow,^^  Umber ,^^  Laquer/^  and 
Burian  and  Scnur,^*  on  the  other  hand,  who  did  more  careful  work, 

1  Rosenfeld  und  Orgler.  Zur  Behandlung  der  Harnsaure  Diathese.  Centralblatt  fiir 
innere  Medizin,  17,  42  (1896). 

2  C.  Dapper.  Ueber  Harnsaureausscheidung  bei  gesunden  Menschen  unter  verschiedenen 
Emakrungsverhaltnissen.     Berl.  klin.  Wochenschrift,  30,  619  (1893). 

3  J.  Ranke.     Physiol,  des  Menschen,  4t  ed.   (1881). 

«  G.  Bunge.     Lehrb.  d.  physiol.  u.  pathol.  Chem.,  1  ed.,  p.  291  (1887) ;  2d  ed.,  p.  344. 
5  F.  Marez.     Sur    I'origine    de    I'acide    urique    chez    I'homme.     Archives    slaves    de 
Biologie,  3,  207  (1888);     Centralblatt  fiir  die  Wissenschaftl.  Med.,  26,  2  (1888). 

8  E.  Schultz.  Ueber  den  Einfluss  der  Nahrung  auf  die  Ausscheidiing  des  Amidartiger 
Substanzen.     Pfluger's  Archiv,  45,  401  (1889). 

'  Schreiber  und  Waldvogel.  Beitrag  zur  Kenntnis  der  Harnsaureausscheidung  unter 
physiologischen  und  pathologischen  Bedingungen.  Arch,  fiir  exp.  Path.  u.  Pharmak., 
42,  69  (1899). 

s  A.  Taylor.  The  Influence  of  Various  Diets  upon  the  Elimination  of  Uric  Acid  and 
the  Purin  Bases.     Amer.  Journ.  of  Med.  Sciences,  118,  141  (1899). 

9  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschhchen  Stofif- 
wechsel.     I.  Mitteilung.     Pfluger's  Archiv,   80,   241    (1900). 

Ihid.  Das  quantitative  Verhalten  des  menschlichen  Harnpurinausscheidung.  Pfluger's 
Archiv,  94,  273  (1903). 

1"  Kussmanoff.  Ueber  die  Ausscheidung  der  Harnsaure  bei  absoluter  Milchdiat.  Dissert. 
Dorpat  (1885). 

11  Markow.  Zur  Frage  des  Stickstoffumsatze  bei  ausschliessUcher  Milchdiat.  Maly's 
Jahresb.  liber  die  Fortschritte  der  Thierchemie,  18,  296  (1888). 

^  F.  Umber.  Ueber  den  Einfluss  nucleinhaltiger  Nahrung  auf  die  Harnsaurebildung. 
Zeitschr.  fur  kUn.  Med.,  29,  174  (1896). 

13  B.  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  im  Harne  von 
Gesunden  und  Kranken.  Verhandl.  der  14  Kongr.  fiir  innere  Med.,  333  (1896),  Wiesbaden. 

Ueber  die  Beeinflussung  des  Alloxurkorper  (Harnsaure  und  Xanthinbasen)  Ausschei- 
dung durch  Milchdiat  und  tiber  Fettmilch  bei  Gicht.  Berl.  klin.  Wochenschrift,  33,  807 
(1896). 

I''  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stofif- 
wechsel.     I.  Mitteilung.     Pfluger's  Archiv,  80,  241  (1900). 

Ihid.  Das  quantitative  Verhalten  des  menschlichen  Harnpurinausscheidung.  Pfliiger'3 
Archiv,  94,  273  (1903). 


140    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

all  found  that  less  uric  acid  was  excreted  when  part  of  the  meat 
in  the  food  is  replaced  by  milk,  and  Sherman  ^  found  that  there 
is  no  increase  in  the  excretion  of  uric  acid  when  the  diet  is  in- 
creased by  the  addition  of  milk.  Laquer  ^  and  Loewi  ^  found 
that  if  meat  is  replaced  by  a  quantity  of  eucasein,  —  prepared 
from  casein  by  treatment  of  the  latter  with  ammonia,  —  contain- 
ing the  same  amount  of  nitrogen,  the  excretion  of  uric  acid  is 
lowered  considerably. 

It  was  found  further  that  if  meat  is  replaced  by  an  equiv- 
alent quantity  of  other  animal  proteid  material  free  from  purins, 
there  is  a  decreased  excretion  of  uric  acid.  Thus  Rosenfeld  ^ 
found  that  a  replacement  of  part  of  the  meat  food  by  aleuronat, 
sodium  caseinate,  peptone,  or  nutrose,  resulted  in  a  decreased 
excretion  of  uric  acid.  Hirschfeld^  found  that  a  decrease  in 
the  excretion  of  uric  acid  follows  when  meat  is  replaced  by 
milk,  vegetable  proteid,  or  egg.  Chotzen  ^  obtained  the  same 
result  when  he  replaced  the  meat  of  the  food  by  an  equiv- 
alent quantity  of  nutrose.  Hopkins  and  Hope  ^  found  no 
increase  in  the  excretion  of  uric  acid  when  white  of  egg  or 
milk  was  given  to  a  person  who  had  fasted  for  fourteen  hours. 
Hess  and  Schmoll  ^  observed  no  increase  in  the  excretion  of 
uric  acid  after  yolk  of  egg  was  added  to  a  standard  diet,  and 
Burian  and  Schur  ^  could  not  observe  an  increased  excretion 
of  uric  acid  when  vegetables,  milk,  or  eggs  were  added  to  a 
standard  diet. 

1  H.  Sherman.  On  the  Influence  of  Diet,  Muscular  Exertion,  and  Loss  of  Sleep  upon 
the  Formation  of  Uric  Acid  in  Man.     Journ.  Am.  Chem.  Soc,  25,  1159  (1903). 

2  B.  liaquer.  Nachtrag  zu  den  Aussatze  iiber  Herabsetzung  der  Harnsam'eausschei- 
dung  bei  Milchdiat.     Deutsche  kUn.  Wochenschrift,  33,  853  (1896). 

3  J.  Loewi.  Der  Eiweisstoffwechsel  in  einen  Falle  von  Anemia  splenica  und  der  Ein- 
fluss  des  Eukasins  auf  denselben.     Fortschritte  der  Medicin,  14,  689  (1896). 

^  G.  Rosenfeld.  Grvrndziige  der  Behandlung  der  Harnsaurer  Diathese.  Verhandl.  des 
14t  Kongr.  fur  innere  Med.,  321,  Wiesbaden  (1896). 

Harnsaure  u.  Gicht.     Allgem.  medicinische  Centralzeitimg,  65,  789  (1896). 

5  F.  Hirschfeld.  Beitrage  zur  Ernahrungslehre  des  JMenschen.  Virchow's  Archiv, 
114,  301  (1888). 

6  Chotzen.     Inaug.   Dissert.     Breslau,   1897. 

^  F.  Hopkins  and  W.  Hope.  On  the  Relation  of  Uric  Acid  to  Diet.  Journ.  of  Physiol., 
23.  271  (1898). 

8  N.  Hess  und  E.  Schmoll.  Ueber  die  Beziehungen  der  Eiwiess-  und  Paranuklein- 
substanzen  der  Nahrung  zur  Alloxurkorperausscheidung  im  Harne.  Arch.  fiir.  exp.  Path, 
u.  Pharmak.,  37,  243  (1896). 

9  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschUchen  Stofif- 
wechsel.     I.  Mitteilung.     Pfliiger's  Archiv,  80,  241   (1900). 

Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoflwechsel.  II.  Mitteilung.  87, 
239  (1901). 


Physiology  141 

Pfeil/  too,  has  shown  that  food  free  from  piirin  bodies 
does  not  affect  the  excretion  of  uric  acid.  This  author  showed 
that  there  is  an  increase  in  the  rate  of  excretion  of  uric  acid 
within  two  hours  after  changing  from  a  meat-free  to  a  meat 
diet. 

If,  as  we  now  beheve,  the  influence  of  foodstuffs  on  the  excre- 
tion of  uric  acid  is  dependent  entirely,  or  nearly  so,  on  their  con- 
tent in  purin  bodies,  we  should  not  expect  the  amount  of  uric 
acid  in  the  urine  to  stand  in  a  constant  ratio  with  the  total  nitro- 
gen, as  Haig  maintains.  It  will  not  be  necessary  to  call  atten- 
tion to  the  numerous  experiments  directly  showing  this,  for  almost 
any  set  of  experiments  on  different  persons  that  we  can  pick  out 
will  show  it.  Busquet's^  experiment  is  interesting.  He  kept 
a  patient  on  a  limited  diet  for  a  year  and  a  half  to  decrease  his 
weight.  The  patient  lost  32.5  kilos,  and  the  urea  excretion 
decreased  from  28  to  10  grams  per  day,  yet  the  excretion  of  uric 
acid  remained  stationary  at  about  .6  gram  per  day.  When  the 
urea  is  very  low,  the  uric  acid  may  be  slightly  decreased,  too, 
according  to  Folin.^ 

Experiments  during  the  last  half  dozen  years  have  shown  that 
it  is  the  meat  extract  consisting  of  constituents  of  the  meat  which 
are  soluble  in  water  that  gives  the  increased  excretion  of  uric 
acid.  Strauss  *  found  that  50  grams  of  meat  extract  gave  an 
increase  of  50  per  cent  in  the  excretion  of  uric  acid  in  one  series 
of  experiments,  and  91  per  cent  in  another  series.  Jerome^ 
observed  a  similar  effect  after  the  use  of  Liebig's  extract.  He 
administered  in  one  case  10  grams  and  in  another  40  grams,  and 
after  both  observed  a  rise  in  the  excretion  of  uric  acid,  —  a  rise  of 
50  per  cent  after  the  40  grams.    Zagari  and  Pace  ^  and  also  Siven  ^ 

1  p.  Pfeil.  Ueber  den  Einfluss  der  Nahrungsaufnahme  auf  die  Ausscheidung  der  Harn- 
saure.     Zeitschr.  fiir  physiol.  Chem.,  40,  1,  1903. 

2  G.  Busquet.  Etude  de  quelque  phenomenes  urolbgiques  constates  dans  une  observa- 
tion d'obesite  avec  hernie  de  la  ligne  blanche  gu^rie  par  vm  traitement  hygi^nique  rational. 
Revue  de  medecine,  12,  572  (1892). 

3  O.  FoUn.  Laws  Governing  the  Chemical  Composition  of  Urine.  Am.  Journ.  of  Physiol., 
13,  66  (1905). 

*  H.  Strauss.  Ueber  die  Beeinflussung  der  Harnsam-e  und  AUoxurbasenausscheidimg 
durch  die  Extractstoff  des  Fleisches.     Berl.  klin.  Wochenschrift,  33,  710  (1896). 

5  W.  Jerome.  The  Formation  of  Uric  Acid  in  Man,  and  the  Influence  of  Diet  on  Its 
Daily  Output.  Joiu-n.  of  Physiol.,  22,  146  (1898).  Also,  Further  Proofs  of  the  Origin 
of  Uric  Acid  from  Nuclein  Compounds.    Journ.  of  Physiol.     25,  98  (1898-99). 

6  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  patogenesi 
e  air  Lndirizzo  terapeutico.     Napoli,  1897;  Centralblatt  fur  innere  Med.,  19,  816  (1S98). 

'  V.  Siven.  Zur  Kenntnis  der  Harnsaurebildung  im  menschlichen  Organismus  unter 
physiologischen  Verhaltnissen.     Skandinav.  Archiv.  f.  Physiol.,  11,  123  (1900). 


142    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

confirmed  these  experiments  with  Liebig's  meat  extract.  Siven  ^ 
found  that  meat  extract  causes  an  increased  excretion  of 
uric  acid,  and  that  the  meat  itself,  after  the  meat  extract 
had  been  separated  from  it,  does  not  give  an  increased  ex- 
cretion. 

The  small  quantity  of  nucleoproteid  found  in  meat  could  not, 
as  Brandeburg  ^  protested,  account  for  the  effect  of  meat  in  in- 
creasing the  excretion  of  uric  acid.  We  have  seen  that  meat 
does  contain  free  purin  bases,  especially  hypoxanthin,  but  it  was 
not  until  Minkowski  ^  showed  that  free  hypoxanthin  and  xanthin 
can  increase  the  excretion  of  uric  acid  when  taken  in  the  food 
that  we  could  definitely  attribute  the  effect  of  meat  on  the  uric 
acid  excretion  to  the  free  purin  bodies  contained  in  it.  Burian 
and  Schur*  have  shown  that  the  quantity  of  purin  bases  in 
meat  is  sufficient  to  account  for  the  difference  in  the  amount 
of  uric  acid  excreted  on  a  mxeat  diet  and  on  a  diet  free  from 
meat. 

According  to  Klemperer,^  fish,  like  meat,  causes  increased  ex- 
cretion of  uric  acid. 

It  seems  plain,  then,  that  meat  and  glandular  organs  rich  in 
cells  give  an  increase  in  the  excretion  of  uric  acid  by  virtue  of 
the  content  of  these  foodstuffs  in  purin  bases,  either  free  or 
combined.  The  bases  are  to  some  extent  oxidized  to  uric  acid 
in  the  body.  The  detailed  consideration  of  the  oxidation  of 
the  individual  purin  bodies  and  the  relative  importance  of  the 
uric  acid  derived  from  the  purin  bodies  of  the  food  will  be  discussed 
later. 

The  Relative  Quantity  of  Uric  Acid  from  the  Food  and 
THAT  FROM  THE  BoDY  TISSUES. — We  See,  then,  that  the  purin 
bodies  and  those  compounds  from  which  purin  bodies  can  be 
obtained  by  hydrolytic  splitting  can  serve  as  a  source  for  uric  acid 
in  the  mammal  organism.     On   the   other   hand,    it    has    been 

1  V.  Siven.  Zur  Kenntnis  der  Harnsaurebildung  im  menschlichpn  Organismus  unter 
physiologischen  Verhaltnissen.     Skandinav.  Archiv.  f.  Physiol.,  11,  123  (1901). 

2  C.  Brandeburg.  Ueber  die  diagnostiche  Bedeutung  der  Harnsaure  und  Xanthinbasen 
im  Urin.     Berl.  klin.  Woohenschrift  33,  137  (1896). 

3  O.  Minkowski.  Untersuchungen  zur  Physiologic  und  Pathologic  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  cxp.  Path,  und  Pharmak.,  41,  375  (1898). 

*  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     Pfliiger's  Archiv,  80,  241  (1900). 

6  G.  Klcmpcrer.  1st  Fischkort  rathsamer  als  Fleisch  bei  harnsaurer  Diathese  und 
Nephritis.     Thcrapie  der  Gegenwart,  Neue  Folge  II,  428  (1901). 


Physiology  143 

shown  by  Schreiber  and  Waldvogel/  Tuczek,^  Lo  Monaco/'^  and 
others  that  in  man,  at  any  rate,  uric  acid  is  excreted  during 
starvation,  and  by  Cario  *  and  by  von  Noorden  ^  that  the  excre- 
tion is  increased  in  inanition  so  that  we  can  come  to  the  view 
first  expressed  by  Camerer,^  that  the  uric  acid  excreted  comes 
from  two  sources,  —  the  food  and  the  body  cells.  Wiener  ^  has 
shown  that  in  the  dog  practically  no  uric  acid  is  excreted  in 
the  urine  unless  purin  bodies,  nuclein,  or  nucleoproteids  are 
given  in  the  food. 

The  Endogenous  Uric  Acid.  —  Since  it  has  become  firmly 
established  that  some  of  the  uric  acid  excreted  by  man  comes 
from  the  food  and  some  from  the  body  tissues,  attempts  have 
been  made  to  determine  what  proportion  of  the  uric  acid  comes 
from  each  source.  Camerer^  believed  that  we  cannot  tell  how 
much  of  the  uric  acid  comes  from  the  food  and  how  much  from 
the  tissues.  He  thinks  it  probable  that  purin  bodies  are  found 
in  all  nitrogenous  food,  and,  further,  that  if  we  did  find  food 
free  from  purin  bodies  and  feed  a  patient  upon  it,  some  of  the 
uric  acid  excreted  at  that  time  might  be  derived  from  purin 
bodies  eaten  a  few  days  before  but  not  oxidized  immediately  and 
excreted.^  Schreiber  and  Waldvogel  ^  determined  the  uric  acid 
excreted  by  two  men  who  starved  for  three  days.  On  the  third 
day  they  found  .197  and  .205  grams  respectively.  They  assumed 
that  the  amount  of  uric  acid  excreted  during  starvation  repre- 
sents that  which  comes  normally  from  the  body,  and  concluded 
from  their  two  experiments  that  the  amount  of  uric  acid  derived 
from  the  body  tissues  is  constant,  not  dependent  on  the  individual, 
and  is  approximately  .20   gram  per  day.     Since,   on   the   same 

1  Schreiber  und  Waldvogel.  Beitrag  zur  Kenntnis  der  Harnsaureausscheidung  imter 
physiologischen  iind  pathologischen  Verhaltnissen.  Arch,  fiir  exp.  Path.  u.  Pharmak., 
42,  69  (1899). 

2  F.  Tuczek.  Mitteilung  v.  Stoffw.  Untersuch.  b.  Geisteskranken.  Medicin.  Central- 
blatt   (1885). 

3  Lo  Monaco.  Bollet  della  Societ.  Lancis.  degli  de  Roma,  Vol.  14,  parte  2,  p.  102  (1894). 
Cited  by  Burian  and  Schur.     Pfliiger's  Arehiv,  80,  241  (1900). 

*  Cario.  Ueber  d.  Einfluss  d.  Fiebers  und  d.  Inanition  anf  d.  Ausscheidvmg  d.  Harn- 
saure.     Gottingen,  37  (1888). 

5  von  Noorden.     Lehrbuch  der  Pathologic  des  Stoffwechsels,  168. 

s  W.  Camerer.  Harnsaure,  Xanthinbasen,  und  Phosphorsaure  im  menschlichen  Urin. 
Zeitschr.  fur  Biol.,  33,  139  (1896). 

'  H.  Wiener.  Ueber  synthetische  BUdung  der  Harnsaure  im  Tierkorper.  Beitrage 
zur  chemischen  Physiologie  und  Pathologie,  2,  42  (1902). 

*  W.  Camerer.  Beitrag  zur  Erforschung  der  Stickstoffhaltigen  Bestandtheile  des  mensch- 
lichen Urins  insbesondere  der  Sogennanten  Alloxurkorper.  Zeitschr.  fiir  Biol.,  35,  206 
(1897). 


144   The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

food,  different  individuals  excrete  different  amounts  of  uric 
acid,  they  concluded  that  the  amount  of  uric  acid  derived 
from  the  food  depends  not  only  on  the  food,  but  also  on  the 
individual. 

Burian  and  Schur  ^  carried  out  a  series  of  experiments  in  which 
they  determined  the  "  endogenous  "  uric  acid  of  the  urine  and 
the  "  exogenovis,"  as  they  call  respectively  the  uric  acid  coming 
from  the  body  cells  and  the  uric  acid  coming  from  the  food. 
These  authors  maintain  that  the  uric  acid  excreted  during  starva- 
tion cannot  be  considered,  as  Schreiber  and  Waldvogel  consider 
it,  the  endogenous  uric  acid.  Starvation  is  not  a  physiological 
condition.  Lo  Monaco  ^  found  that  the  professional  faster  Succi 
excreted  .250  gram  uric  acid  on  the  twenty-fifth  day  of  starva- 
tion, an  amount  greater  than  Schreiber  and  Waldvogel  found. 
Further,  Ranke  ^  and  Hofmann  ^  found  more  uric  acid  excreted 
during  use  of  a  diet  free  from  purin  bodies  than  during  starv- 
ation. According  to  Burian  and  Schur  ^  the  endogenous  uric  acid 
may  be  considered  equal  to  the  amount  excreted  when  the  patient 
is  fully  nourished,  but  receives  in  his  food  no  purin  bodies,  either 
free  or  combined.  The  value  of  the  endogenous  uric  acid  deter- 
mined in  this  way  is  different  for  different  individuals,  but  con- 
stant at  different  times  for  the  same  individual  if  he  does  not 
considerably  change  his  mode  of  life.  The  exogenous  uric  acid, 
on  the  other  hand,  is,  according  to  them,  dependent  solely  on  the 
amount  and  kind  of  purin  bodies  in  the  food.  It  is  not  different 
for  different  individuals  if  they  eat  the  same  kind  and  quantity 
of  food. 

.  These  authors  found  that  by  changing  the  diet  from  one  con- 
sisting of  milk,  cheese,  and  eggs,  high  in  proteid,  to  a  milk- 
cheese-eggs  diet  low  in  proteid,  and  then  to  a  vegetable  diet 
there  is  no  change  in  the  amount  of  uric  acid  excreted.  Hall  ^ 
found  that  if  the  amount  of  proteid  in  a  diet  free  from  purin 
bodies  kept  constant,  but  the  value  in  calories  per  day  be  consid- 

1  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  StofiE- 
wechsel.     I.  Mitteilung.     Pfluger's  Archiv,  80,  241   (1900). 

2  Lo  Monaco.  Bollet  della  Societ.  Lancis.  degli  de  Roma,  Vol.  14,  parte  2,  p.  102  (1894). 
Cited  by  Burian  and  Schur. 

3  J.  Ranke.  Kohlenstoff-  und  Stickstoff-ausscheidung  des  ruhenden  Menschen.  Arch, 
f.  Anat.  u.  Physiol.,  301  (1862). 

*K.  Hoffman.     Lehrb.  d.  Zoochemie,  446,  Wien  (1879). 

5  W.  Hall.  The  Purin  Bodies  of  Food  Stuffs.  Inaug.  Dissert.,  Owens  College,  Man- 
chester, Eng.  (1902). 


Physiology  145 

erably  changed,  the  amount  of  uric  acid  in  the  urine  remains 
constant.  According  to  Hirschfeld's  results/  the  value  in  calories 
of  the  food  and  the  amount  of  proteid  in  the  food  may  both  be 
changed  without  influencing  the  amount  of  uric  acid  excreted. 
Hall  ^  and  Rockwoocl,^  too,  found  that  the  amount  of  purin 
bodies  in  the  urine  is  independent  of  the  c{uantity  of  proteid 
and  of  the  heat  value  of  the  food.  The  uric  acid  excreted 
seems  to  be  independent  of  the  quality  and  the  quantity  of 
the  food  within  wide  limits,  so  long  as  the  food  is  free  from 
purin  bodies.  According  to  Folin,''  the  endogenous  uric  acid 
is  not  absolutely  constant  in  any  individual.  When  the  total 
nitrogen  excretion  is  exceedingl}^  low,  the  endogenous  uric  acid 
is  somewhat  decreased. 

In  a  series  of  experiments  on  Burian  in  May,  1899,  lasting 
twenty  days,  Burian  and  Schur^  found  an  average  quantity  of 
.199  gram  endogenous  purin  nitrogen  in  the  urine  per  day.  In 
a  series  of  experiments  in  November,  1899,  lasting  four  days, 
the  average  amount  of  purin  nitrogen  excreted  was  .200  gram. 
In  a  third  series,  in  December,  1900,  lasting  nine  days,  .199 
gram  per  day  was  the  average  amount  of  purin  nitrogen 
excreted.  Siven^  likewise  found  the  endogenous  uric  acid 
in  the  urine  individually  constant  and  independent  of  the 
food. 

In  experiments  on  five  different  people  Burian  and  Schur  found, 
respectively,  .203,  .153,  .122,  .155,  and  .137  grams  endogenous  uric 
'acid  per  day.  They  pointed  out  experiments  of  Hirschfeld,^  Her- 
ringham  and  Davies,^  Camerer,^  Schreiber  and  Waldvogel,^  and 

1 F.  Hirschfeld.  Beitrage  zur  Ernahrungslehre  des  Menschen.  Virchow's  Archiv, 
114,  301  (1888). 

2 1.  W.  Hall.  The  Purin  Bodies  of  Food  Stuffs.  Inaug.  Dissert,  Owens  College,  Man- 
chester, Eng.  (1902). 

3  E.  Rockwood.     The  Ehmination  of  Endogenous  Uric  Acid.     Am.  Journ.  of  Physiol. 

12,  38,  1904. 

*  O.  Folin.     Laws  Governing  the  Chemical  Composition  of  Urine.    Am.  Journ.  of  Physiol., 

13,  66  (1905). 

5  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  m.enschlichen  Stoff- 
wechsel.     1.  Mitteilung.     Pfliiger's  Archiv,  80,  241  (1900). 

<>  V.  Siven  (3).  Zur  Kenntnis  der  Harnsaurebildung  im  menschUchen  Organismus  unter 
physiologischen  Verhaltnisse.     Skandinav.  Archiv.  f.  Physiol.,  11,  123  (1901). 

'W.  Herringham  and  H.  Dalies.  On  the  Excretion  of  Uric  Acid  and  Urea.  Jouru. 
of  Physiol.,  12,  475  (1891). 

8  W.  Camerer.  Gesammtstickstoff,  Harnstoff,  Harnsaure,  und  Xanthinkorper  im 
menschUchen  Urin.     Zeitschr.  ftir  Biol.,  28,  72  (1891). 

3  Schreiber  und  Waldvogel.  Beitrag  zur  Kenntnis  der  Harnsiiureausscheidung  unter 
physiologischen  und  pathologischen  Verhiiltnissen.  Arch,  filr  exp.  Path.  u.  Pharmak., 
42,  69  (1899). 


146    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Minkowski/  in  which  the  endogenous  uric  acid  was,  respectively, 
.153  gram,  .200  gram,  .132  gram,  .145  gram,  and  .075  gram. 
Rockwood,^  too,  found  the  endogenous  uric  acid  different  for 
different  individuals.  From  these  results  we  can  see  that  the 
endogenous  uric  acid  is  different  for  different  individuals. 

It  might  be  well  to  state  at  this  point  that  Burian  and  Schur 
determined  both  the  uric  acid  and  the  total  purin  bodies  of  the 
urine.  In  drawing  their  conclusions  they  speak  chiefly  of  the 
purin  bodies  as  a  whole.  All  their  conclusions  concerning  the 
endogenous  purin  nitrogen,  however,  apply  equally  well  to  the 
endogenous  uric  acid,  as  can  be  seen  from  their  tables.  It  is  well 
to  speak  of  this  point,  for  although  the  purin  bodies  of  the  urine 
make  up  but  a  very  small  fraction  of  the  total  amount  of  purin 
bodies,  yet  we  know  that  purin  bases  are  found  in  the  feces  as 
w^ell.  Then,  again,  His  and  Hagen  ^  have  criticized  the  accuracy 
of  all  the  methods  so  far  recommended  for  the  determination  of 
purin  bases.  These  objections  do  not  apply  to  the  conclusions 
concerning  uric  acid,  however. 

Loewi*  concluded  from  two  series  of  experiments  which  he 
performed  that  both  the  endogenous  and  exogenous  uric  acid 
excreted  are  dependent  entirely  upon  the  amount  of  purin  bodies 
absorbed  from  the  food.  He  assumed,  however,  that  the  amount 
of  P2O5  excreted  is  a  measure  of  the  nuclein  and  purin  bodies 
absorbed.     In  his  two  series  of  experiments  he  did  find  the  ratio 


approximately  the  same.     The  uric  acid  in  the  two 


uric  acid 

series  varied  considerably,  however,  and  in  fact,  Burian  and  Schur 
were  able  to  use  the  results  as  confirmation  of  their  own  conclu- 
sions. We  have  seen  that  the  excretion  of  phosphoric  acid  is 
not  a  measure  of  the  nuclein  absorbed. 

In  a  second  article,^  Loewi  criticized  Burian  and  Schur  for  calling 
the  uric  acid  excreted  during  use  of  a  diet  containing  milk  wholly 


1  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

2  E.  Rockwood.  The  elimiaation  of  endogenous  uric  acid.  Am.  Journ.  of  Physiol., 
12,  38  (1904). 

3W.  His  und  W.  Hagen.  Kritische  Untersuchxingen  uber  den  Nachweis  von  Harn- 
saure und  Purinbasen  im  Blut,  und  in  thierischen  Organen.  Zeitschr.  fiir  physiol.  Chem., 
30,  350  (1900). 

*  O.  Loewi.  Beitrage  zur  Kenntnis  der  Nukleinstoffwechsel.  I.  Mitteilung.  Archiv. 
fur  exp.  Path.  u.  Pharmak.,  44,  1  (1901). 

^  Ibid.  Untersuchungen  iiber  den  Nukleinstoffwechsel.  II.  Mitteilung.  Archiv. 
fiir  Exp.  Path.  u.  Pharmak.,  45,  157  (1901). 


Physiology  147 

endogenous,  since  these  authors  themselves  ^  have  found  that 
the  amount  of  nucleoproteid  increases  in  sucklings  as  they  grow 
older,  although  they  obtain  nothing  but  milk,  as  food.  This  is 
not  an  objection  against  the  conclusions  of  Burian  and  Schur 
regarding  the  endogenous  uric  acid,  for  milk  does  not  give  a 
greater  excretion  of  uric  acid  than  any  other  food  not  containing 
purin  bodies.  The  uric  acid  derived  from  the  nucleoproteid 
synthesized  during  use  of  a  milk  diet  is  truly  endogenous. 

Another  criticism  of  Loewi  is  that  the  endogenous  uric  acid  as 
determined  by  Burian  and  Schur  is  a  "  starvation  value,"  com- 
parable with  the  "  starvation  value  "  of  NaCl  or  nitrogen.  We 
know  that  when  NaCl  is  withheld  from  the  food,  some  NaCl  is 
excreted  in  the  urine.  This  is  derived  from  the  body  tissues,  but 
is  gTeater  than  the  amount  ordinarily  derived  from  the  tissues. 
The  organism  tries  to  make  up  for  the  poverty  of  the  food  in  NaCl. 
In  NaCl  or  proteid  starvation  we  know  that  in  a  short  time  sick- 
ness and  death  result.  This  is  not  the  case  when  purin  bodies 
are  withheld  from  the  food.  Sucklings  excrete  very  large  quan- 
tities of  uric  acid  on  a  diet  free  from  purin  material.  Burian  and 
Schur  ^  in  a  recent  article  answer  Loewi's  objection  and  say  that 
we  cannot  consider  a  diet  such  as  one  free  from  purin  bodies 
which  maintains  a  person  in  good  health  for  an  indefinitely  long 
period  in  any  sense  a  "  stari^ation  diet." 

A  principal  difference  between  the  endogenous  uric  acid  and 
the  endogenous  proteids  and  inorganic  salts  used  up  is  that  the 
nucleoproteid  of  the  body  cells,  which  is  probably  the  source  of 
the  endogenous  uric  acid,  can  be  synthesized  from  material  free 
from  purin  bodies.  Thus  Tichomiroff  ^  found  by  analyis  of 
fresh-laid  eggs  of  certain  insects  (Bombyx  Mori.  L.)  less  than 
0.02  per  cent  of  hypoxanthin  and  guanin,  and  no  xanthin.  After 
these  eggs  had  partly  developed  by  standing  through  the  winter, 
he  found  0.13  per  cent  hypoxanthin  and  guanin  and  0.10  per  cent 
xanthin.  These  purin  bodies  were  in  the  cell  nuclein.  In  the 
nuclein   of   fresh-laid  hen's  eggs  (pseudonuclein)  Kossel*    could 

1  Burian  und  Schur.  Ueber  Nukleinbildung  im  Saugethierorganismus.  Zeitsebx.  fur 
physiol.  Chem.,  23,  55  (1897). 

^  Ibid.  Das  quantitative  Verhalten  der  menschlichen  Harnpurinausscheidung. 
Pfluger's  Archiv,  94,  273  (1903). 

3  A.  Tichomiroff.  Chemische  Studien  iiber  die  Entwicklung  der  Insekteneier.  Zeitschr. 
fiir  physiol.  Chem.,  9,  518  (1885). 

^  A.  Kossel.  Weitere  Beitrage  zur  Chemie  des  Zellkernes.  Zeitschr.  fiir  physiol. 
Chem.,  10,  248  (1886). 


148    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

find  no  purin  bodies.  After  fifteen  days'  incubation  he  found 
0.28  per  cent  guanin  and  0.66  per  cent  hypoxanthin.  Real  nu- 
cleoproteid  had  been  formed  from  compounds  free  from  purin 
bodies.  Burian  and  Schur^  performed  a  series  of  experiments 
in  which  they  determined  the  amount  of  purin  bodies  and  real 
nuclein  in  newborn  rabbits  and  puppies,  and  again  in  animals  of 
about  the  same  weight  and  from  the  same  litter  after  they  had 
lived  on  milk  for  a  feAv  weeks.  It  was  found  in  all  cases  that  there 
was  a  very  great  increase  in  the  quantity  of  nuclein.  From  these 
results  we  can  see  that  nucleoproteid  can  be  synthesized  in  the 
animal  organism  from  material  free  from  purin  bodies. 

The  last  objection  brought  up  by  Loewi  against  the  statements 
of  Burian  and  Schur  is  that  they  are  not  justified  in  "  schema- 
tizing "  physiological  processes  as  they  have  done.  This  objec- 
tion Loewi  applied  especially  to  the  statements  of  Burian  and 
Schur  concerning  the  exogenous  uric  acid,  which  we  will  take  up 
next.  Burian  and  Schur,  however,  have  maintained  that  they 
merely  stated  observed  facts  and  did  not  offer  any  hypotheses.^ 

Siven  ^  has  likewise  found  the  endogenous  uric  acid  constant 
for  any  one  person  and  independent  of  the  food. 

Uric  Acid  from  the  Purin  Bodies  of  the  Food.  —  We  have  seen 
that  some  of  the  uric  acid  excreted  is  derived  from  the  purin  bodies 
of  the  food.  In  dogs,  Wiener*  has  shown  that  this  is  the  source 
of  practically  all  the  uric  acid  in  the  urine.  Burian  and  Schur  ^ 
have  shown  that,  in  man,  the  exogenous  uric  acid  depends  solely 
on  what  purin  bodies  are  present  in  the  food  and  their  quantity. 
A  certain  fraction  of  the  xanthin  administered,  for  example, 
appears  in  the  urine  as  uric  acid.  A  certain  other  fraction  of 
the  adenin  administered  appears  as  uric  acid.  The  fraction 
of  each  purin  body  which  appears  in  the  urine  as  uric  acid  is 
practically  the  same  for  all  persons.     Minkowski^  had  come  to  the 

'  R.  Burian  und  H.  Schur.  Ueber  Nukleinbildung  im  Saugethierorganismus.  Zeitschr. 
fiir  physiol.  Chem.,  23,  55  (1897). 

2  Ibid.  Das  quantitative  Verhalten  der  menschlichen  Harnpurinausscheidung.  Pfliiger's 
Archiv,  94,  273  (1903). 

3  V.  Siven.  Zur  Kenntnis  der  Harnsaurebildung  im  menschlichen  Organismus  unter 
physiologischen  Verhaltnissen.     Skandinav.  Archiv.  fiir  Physiol.,   11,   123   (1901). 

*  H.  Wiener.  Ueber  synthetische  Bildung  der  Harnsaure  im  Thierkorper.  Beitrage 
zur  chemischen  Physiologie  und  Pathologie,  2,  42  (1902). 

5  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     I.  MitteUung.     Pfliiger's  Archiv,  80,  241  (1900). 

6  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Archiv.  fur  exp.  Path,  und  Pharmak.,  41,  375  (1898). 


Physiology  149 

conclusion  that  formation  of  uric  acid  from  purin  bodies 
depended  on  whether  these  bodies  were  free,  or  combined  loosely, 
or  firmly  in  the  nucleins  and  nucleoproteids.  He  took  this  stand 
because  his  experiments  seemed  to  show  that  adenin  does  not 
become  oxidized  to  uric  acid  in  the  organism  when  administered 
as  free  adenin,  whereas  it  is  well  known  that  the  adenin  com- 
bined in  the  nucleoproteid  of  calves'  thymus  does  become  oxi- 
dized to  uric  acid.  Burian  and  Schur  ^  showed  that  in  the  case 
of  hypoxanthin,  at  any  rate,  the  same  fraction  of  hypoxanthin  is 
oxidized  to  uric  acid  in  the  body  whether  it  is  administered  in 
the  free  condition  or  combined  as  nucleic  acid,  nuclein,  and 
nucleoproteid. 

Before  considering  the  quantitative  experiments  of  Burian 
and  Schur  and  others  on  the  behavior  of  the  individual  purin 
bodies  in  the  organism,  it  will  be  well  to  say  a  word  in  regard 
to  the  absorption  of  nucleoproteids,  nucleins,  nucleic  acid,  and 
the  purins,  and  the  occurrence  of  these  substances  in  the  feces. 

Absorption  of  Nuclein  and  Purin  Bodies 

Direct  experiment  by  Popoff  ^  showed  that  nuclein  is  absorbed 
in  large  part  in  the  small  intestine.  In  Gumlich's  ^  experiments, 
nuclein  w^as  absorbed,  for  he  found  it  in  the  chyme.  Bokay  *  alone 
stated  that  nuclein  is  not  absorbed.  He  based  his  statement  on 
the  fact  that  he  found  nuclein  in  the  feces.  Since,  as  we  shall  see, 
nuclein  in  the  feces  may  be  derived  from  the  body  tissue  itself, 
Bokay's  conclusions  are  of  no  value.  The  experiments  of  Burian 
and  Schur  ^  seem  to  indicate  that  xanthin  and  hypoxanthin, 
free  or  combined,  are  practically  completely  absorbed.  These 
authors  found  that  the  same  fraction  of  these  bodies  is  changed 
to  uric  acid  in  the  organism,  whether  the  base  is  free  or  combined 
and  within  wide  limits,  whether  large  or  small  amounts  are  ad- 
ministered. 

Hall  ^  found  50  per  cent  of  the  guanin  taken  per  os  in  the  feces. 

1  R.  Burian  iind  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stofif- 
wechsel.     I.  Mitteilung.     Pfliiger's    Archiv,    80,    241    (1900). 

2  P.  Popoff.  Ueber  die  Einwirkung  von  eiweissverdauenden  Fermenten  auf  die  Nucleln- 
Etoffe.     Zeitschr.  fiir  physiol.  Chem.,   18,  533  (1894). 

3  Gumlich.  Ueber  die  Auf  nab  me  der  Nucleine  in  den  thierischen  Organismus.  Zeitschr. 
fiir  physiol.  Chem.,  18,  508  (1894). 

^  A.  Bokay.  Ueber  die  VerdauUchkeit  des  Nucleins  und  Lecithin.  Zeitschr.  fiir 
physiol.  Chem.,  1,  157  (1877). 

'  I.  Hall.     The  Purin  Bodies  of  Food  Stuffs.     2d  ed.,  Manchester,  Eng.,  1903. 


150    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Xanthin,  thymus,  and  nucleic  acid  cause  but  a  slight  increase  in 
the  purin  bodies  of  the  feces.  Hypoxanthin  seems  to  be  com- 
pletely absorbed. 

Salkowski  ^  found  that  in  dogs  a  variable  part,  in  one  case  20 
per  cent,  in  another  nearly  50  per  cent,  of  the  uric  acid  adminis- 
tered per  OS  is  absorbed.  Some  is  excreted  as  allantoin,  some 
as  urea.  In  rabbits  more  than  half  is  absorbed.  This  is  mostly 
excreted  as  urea.  A  small  part  is  excreted  unchanged.  Sal- 
kowski fed  the  animal  on  a  diet  in  which  the  nitrogen  and  sulphur 
were  constant.  An  addition  of  uric  acid  to  the  food  gave  an 
increase  in  the  nitrogen  in  the  urine.  Determinations  of  sulphur 
in  the  urine  showed  that  the  decomposition  of  body  proteid  was 
constant.  The  increased  nitrogen  in  the  urine  was  a  measure 
of  the  absorption  of  uric  acid  according  to  Salkowski. 

The  Purin  Bodies  of  the  Feces 

Weintraud^  was  the  first  to  study  the  purin  bodies  of  the 
feces.  This  author  found  from  .100  to  .500  gram  of  purin 
bodies  per  day,  free  or  combined,  in  nuclein  in  human  feces. 
The  average  quantity  was  .130  gram.^  Since  these  purin  bodies 
are  found  in  the  feces,  even  when  the  food  contains  no  purin 
bodies,  and  even  in  the  meconium  of  the  newborn,^  Weintraud 
expressed  the  view  that  they  come  from  the  mucous  mem- 
brane of  the  alimentary  canal.^  These  purin  bodies  do  not 
come  from  bile,  for  they  are  found  in  feces  free  from  bile. 
Petren^  has  confirmed  this  fact,  and  further,  according  to 
Schittenhelm,^  bile  is  free  from  purin  bodies.  In  leukemia,  when 
there  is  increased  excretion  of  uric  acid,  there  is  likewise  an  in- 
creased quantity  of  purin  bodies  in  the  feces,  according  to  Wein- 
traud. Schittenhelm  ^  could  not  confirm  this.  Since  nuclein 
or  purin  bodies  given  by  the  mouth  or  by  the  rectum  are  absorbed 

1  E.  Salkowski.  Ueber  das  Verhalten  in  der  Magen  eingefiihrten  Harnsaure  im.  Organ- 
ismus.     Arch.  f.  exp.  Path.  u.  Pharmak.,  35,  495  (1900). 

-  W.  Weintraud.  Zur  Enstehung  der  Harnsaure  im  Saugethiereorganismus.  Verhandl. 
des  14  Kongr.  fiir  innere  Med.,  190  (1896),  Wiesbaden,  and  Wiener  khn.  Rundschau  (1896), 
No.   1,  2. 

^  Ibid.     Beitrage  zum  Stoffwechsel  der  Gicht.     Charite  Annalen,  275  (1895). 

*  Ibid.  Ueber  Harnsaurebildung  beim  menschen.  Vortrag.  geh.  in  der  physiol. 
Gesellsch.  zu  Berlin,  Marz,  1895,  and  Du  Bois  Archiv,  382  (1895). 

5  K.  Petr^n.  Nachtrag  zur  Mitteilung  iiber  das  Vorkommen  der  Xanthinbasen  in  den 
Faces.     Skandinav.  Archiv  fiir  Physiol.,  9,  412  (1899). 

^  A.  Schittenhelm.  Die  Purinkorper  der  Faces  nebst  Untersuchungen  iiber  die  Purin- 
basen  der  Darmwand,  der  Galle  und  des  Panki-eassaftes.  Arch,  fur  klin.  Med.,  81,  423  (1904). 


Physiology  151 

and  excreted  as  uric  acid,  Weintraiid  thinks  these  nucleins  and 
piirin  bodies  come  from  the  intestinal  membranes  and  serve  as 
the  source  of  the  endogenous  uric  acid,  for  after  feeding  calves' 
thymus  he  could  not  find  an  increased  quantity  of  xanthin  bases 
in  the  feces. ^  Weintraud  states  that  in  infants'  feces,  in  which 
oxidation  processes  are  found,  corresponding  to  the  presence  of 
biliverdin  (oxidized  bilirubin) ,  there  is  chiefly  uric  _  acid  and 
almost  no  purin  bases.  In  adults'  feces,  on  the  other  hand, 
where  we  have  hydrobilirubin  (reduced  bilirubin),  practically 
all  purin  bodies  are  present  as  bases  and  only  in  traces  as  uric  acid. 
When  calomel  is  administered,  however,  we  get  in  adults'  feces 
an  oxidation  to  biliverdin  and  uric  acid.  The  work  of  Weintraud 
was  soon  confirmed  by  Brandeburg,^  who  agreed  with  Weintraud 
in  his  conclusions. 

Petren^  found  about  .15  per  cent  of  purin  bases  in  dry  feces. 
This  was  1.8  per  cent  of  the  total  nitrogen,  and  is  more  than  is  in 
the  urine.  These  purin  bases  do  not  come  from  the  food,  for 
they  are  found  in  feces  when  a  person  lives  on  a  milk  diet  free 
from  nuclein  and  purin  bodies.  According  to  Hall/  there  is  from 
.01  to  .03  gram  of  purin  nitrogen  in  the  feces  for  one  day.  Schit- 
tenhelm  ^  states  that  the  quantity  of  purin  bodies  varies  from 
.027  to  .285  gram  per  day. 

Micko  ^  found  nuclein  in  the  feces.  Ury  ^  likewise  found 
nuclein  to  the  extent  of  one  third  of  one  per  cent.  Parker  ^  states 
that  there  are  no  free  purin  bases  in  the  feces,  only  those  com- 
bined in  nucleins.  In  this  he  was  at  first  confirmed  by  Hall,^  but 
more  recently  Hall  ^°  has  stated  that  guanin  and  adenin  may 

1  Weintraud.  Ueber  die  Ausscheidung  von  Harnsaure  und  Xanthinbasen  durch  die 
Faces.     Centralblatt  fur  innere  Med.,  16,  433  (1895). 

2  C.  Brandeburg.  Ueber  die  diagnostische  Bedeutung  der  Harnsaure  und  Xanthinbasen 
in  Urin.     Berl.  klin.  Wochenschrift,  33,  137  (1896). 

3  K.  Petr^n.  Ueber  das  Vorkommen,  die  Menge,  vind  die  Abstammung  der  Xanthin- 
basen in  den  Faces.     Skandinav.  Archiv.  fiir  Physiol.,  8,  315  (1898). 

*  I.  Hall.  A  Contribution  to  the  ELnowledge  of  the  Purin  Bodies  of  Human  Feces  in 
Health  and  Disease.     Journ.  of  Path,  and  Bact.,  9,  246  (1904). 

5  A.  Schittenhelm.  Die  Purinkorper  der  Faces  nebst  Untersuchungen  iiber  die  Purin- 
basen  der  Darmwand,  der  Galle,  und  der  Pankreassaft.  Archiv  fiir  klin.  Med.,  81,  423  (1904). 

6  K.  Micko.  Vergleichende  Untersuchungen  iiber  die  bei  Plasmon  und  Fleischnahrung 
ausgeschiedenen  Kote.     Zeitschr.  fiir  Biol.,  39,  430  (1900). 

7  H.  Ury.  Zur  Methodik  der  Fakaluntersuchungen.  Deutsche  med.  Wochenschrift,  27, 
718(1901). 

^  W.  Parker.  The  Occurrence  and  Origin  of  the  Xanthin  in  the  Feces.  Am.  Journ. 
of  Physiol.,  4,  83  (1901). 

9  I.  HaU.     The  Purin  Bodies  of  Food  Stuffs.     2d  ed.,  Manchester,  Eng.,  1903. 

'''  Ibid.  A  Contribution  to  the  Knowledge  of  the  Purin  Bodies  of  the  Feces  in  Health 
and  Disease.     Journ.  of  Path,  and  Bact.,  9,  246  (1904). 


152    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

exist  free  in  the  feces.  According  to  Schittenhelm,  the  purin  is 
formed  in  the  feces,  both  free  and  combined  in  nuclein  and  nucleic 
acid,  the  free  purin  bodies  making  up  from  one  third  to  one  fourth 
of  the  total  quantity. 

Kriiger  and  Schittenhelm  ^  found  in  forty-two  days'  feces  2.363 
grams  guanin,  1.88  grams  adenin,  .112  gram  xanthin,  and  .300 
gram  hypoxanthin,  an  average  of  .11  gram  of  purin  bases  per 
day.  Galdi  ^  studied  the  excretion  of  uric  acid  and  the  purin 
bases  in  the  urine  and  feces  in  leukemia.  The  results  of  these 
authors  are  not  comparable,  for  they  used  different  methods  of 
determination.  It  has  been  a  question  whether  any  of  the 
methods  .used  by  these  authors  for  the  determination  of  purin 
bases  in  feces  are  accurately  quantitative.^  Further,  it  is 
probable  that  the  aminopurins  change  to  oxypurins  under  the 
influence  of  the  bacteria  of  the  feces,  so  that  the  relative 
proportion  of  the  different  individual  purin  bodies  is  not 
important. 

According  to  Schmidt  and  Strassburger,*  about  a  third  of  the 
dry  substance  of  feces  is  composed  of  bacteria,  and  since  nuclein 
has  been  found  in  bacteria  by  Ruppel,^  Galeoth,**  Bendix,^  and 
indeed  by  Schittenhelm  and  Tollens  ^  to  such  an  extent  that  the 
purin  bodies  account  for  about  33  per  cent  of  the  total  nitrogen 
of  the  bacteria,  one  source  of  the  purin  bodies  of  the  feces  is 
established.  Schittenhelm  ^  maintains  that  the  purins  of  the 
bacteria  make  up  a  considerable  portion  of  the  total  purin  nitrogen 
of  the  feces. 

1  M.  Kriiger  und  A.  Schittenhelm.  Die  Purinkorper  der  menschlichen  Faeces.  Zeitschr. 
fur  physiol.  Chem.,  35,  153  (1902). 

2  F.  Galdi.  Ueber  die  Alloxurkorper  im.  Stofiwechsel  bei  Leukamie.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  49,  213  (1903). 

'^  W.  His  und  W.  Hagen.  Kritische  Untersuchungen  liber  den  Nachweis  von  Harnsaure 
und  Purinbasen  im  Blut  imd  in  thierischen  Organen.  Zeitschr.  fiir  physiol.  Chem.,  30, 
350  (1900). 

*  Schmidt  und  Strassburger.     Die  Faces  des  Menschen.     Berlin,  1903. 

5  W.  Ruppel.  Zur  Chemie  der  Tuberkelbazillus.  Zeitschr.  fiir  physiol.  Chem.,  26,  218 
(1899). 

s  G.  Galeoth.  Beitrage  zur  Kenntnis  der  bakterillen  Nukleoproteid.  Zeitschr.  fiir 
physiol.  Chem.,  25,  48  (1898). 

^  E.  Bendix.  Zur  Chemie  der  Bakterien.  Deutsche  med.  Wochenschrift,  27,  18 
(1901). 

8  A.  Schittenhelm  und  C.  Tollens.  Untersuchungen  iiber  den  quantitativen  Anteil  der 
Bakterien  an  Stickstoff  und  Purinbasen  des  Faces.  Zentralbl.  fiir  innere  Medizin,  25,  761 
(1904). 

3  A.  Schittenhelm.  Die  Purinkorper  der  Faces  nebst  Untersuchungen  iiber  die  Purin- 
korper der  Darmwand,  der  Galle,  und  des  Pankreassaftes.  Arch,  fiir  kUn.  Med.,  81,  423 
(1904). 


Physiology  153 

Hall  ^  studied  the  effect  of  diet  on  the  quantity  of  purin  in  the 
feces.  The  greatest  quantity  was  found  on  a  vegetable  diet, 
the  least  on  a  milk  diet.  Parker^  found  a  greater  quantity  of 
purin  bases  in  the  feces  on  a  meat  diet  than  on  a  diet  of  milk  or 
carboh3^drates.  According  to  Schittenhelm,^  the  oxypurins,  xan- 
thin,  and  hypoxanthin,  and  meat,  which  contains  hypoxanthin, 
do  not  cause  an  increase  in  the  quantity  of  purins  in  the  feces 
when  taken  in  the  food,  but  thymus  gland,  which  contains  the 
aminopurin  adenin,  does  increase  the  quantity  of  purins  in  the 
feces.  Schittenhelm's  results  were  confirmed  by  Hall,^  who 
showed  that  meat  and  hypoxanthin,  unless  taken  in  excessive 
quantities,  do  not  affect  the  quantity  of  purins  in  the  feces,  but 
that  thymus  gland,  or  guanin,  or  pancreas  which  contains  guanin, 
taken  in  the  food  do  increase  the  quantity  of  purins  in  the  feces. 
In  fact,  in  some  cases  as  much  as  60  per  cent  of  the  guanin  eaten 
was  found  again  in  the  feces. 

Hall  *  noted  that  in  diarrhoea  and  inflahimatory  conditions  of 
the  digestive  tracts,  the  quantity  of  purin  bases  in  the  feces  is 
increased.  Schittenhelm,^  too,  found  the  purin  bases  in  the 
feces  high  in  diarrhoea  and  low,  on  the  other  hand,  in  cases  of 
constipation  and  disease  of  the  pancreas.  In  the  latter  case  he 
attributes  the  result  to  poor  digestion  of  the  nucleoproteids  of 
the  food. 

In  this  connection  it  may  be  stated  that  Araki^  has  found  a 
nucleic  acid  in  the  mucous  membrane  of  the  small  intestine,  and 
that  Schittenhelm  ^  has  found  adenin  and  guanin  together  with 
smaller  quantities  of  xanthin  and  hypoxanthin  in  the  walls  of 
the  alimentary  canal. 

It  is  possible  that  the  purin  bodies  in  the  feces  may  be  in  part 
simply  excretion  products ,  and  that  the  quantity  in  the  feces  and 

1 1.  Hall.  The  Purin  Bodies  of  Human  Feces  in  Health  and  Disease.  Brit.  Med.  Journ. , 
2,  582  (1903). 

lUd.     The  Purin  Bodies  of  Food  Stuffs.     2d  ed.,  Manchester,  Eng.  (1903). 

Ibid.  A  Contribution  to  the  Knowledge  of  the  Purin  Bodies  of  Human  Feces.  Journ. 
of  Path,  and  Bact.,  9,  246  (1904). 

-  W.  Parker.  The  Occurrence  and  Origin  of  the  Xanthin  in  the  Feces.  Amer.  Journ. 
of  Physiol.,  4,  83  (1901). 

3  A.  Schittenhelm.  Die  Purinkorper  der  Faces  nebst  Untersuchungen  iiber  die  Purin- 
basen  der  Darmwand,  der  Galle,  und  des  Pankreassaftes.  Arch,  fur  khn.  Med.,  81,  423 
(1904). 

*  I.  Hall.  A  Contribution  to  the  Knowledge  of  the  Purin  Bodies  of  Human  Feces  in 
Health  and  Disease.     Journ.  of  Path,  and  Bact.,  9,  246  (1904). 

^  T.  Araki.  Ueber  die  Nucleinsaure  aus  der  Schleimhaut  des  Dunndarms.  Zeitschr. 
fiir  physiol.  Chem.,  .36,  98  (1903).    ■ 


154     The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

urine  may  be  dependent  both  on  the  same  antecedent  cause. 
It  is  known,  for  example,  that  calcium  salts  are  normally  ex- 
creted into  the  intestines  to  some  extent,  and  Bernard  and 
Barreswill  ^  have  found  that  after  kidney  extirpation,  when  the 
urea  is  in  the  blood,  it  becomes  partially  excreted  into  the  intes- 
tines. There  is  no  increased  excretion  of  uric  acid  into  the 
intestines  after  kidney  extirpation.^  In  this  case,  however,  the 
purin  bodies  may  be  destroyed. 

It  may  be  mentioned  too,  that  Schittenhelm  ^  has  found  that 
the  quantity  of  purin  bases  in  feces  decreases  very  much  on 
standing,  and  on  account  of  the  high  content  of  feces  in  bacteria, 
and  the  fact  that  bacteria  found  in  the  feces  will  decompose  the 
purin  bases  from  yeast  nuclein,^  this  author  attributed  the  de- 
crease in  purin  bases  in  feces  to  bacterial  decomposition. 

To  summarize  briefly,  we  may  say  that  the  purin  bodies  of  the 
feces  come  in  large  part  to  the  nucleoproteids  in  the  bacteria. 
A  variable  part,  dependent  on  the  kind  of  food  eaten,  but  gener- 
ally a  small  part,  may  come  from  the  purin  bodies  of  the  food. 
Another  source  of  importance  is  probably  the  mucous  membrane 
lining  the  intestines,  some  of  which  containing  purin  bodies  is 
probably  thrown,  off  and  passes  into  the  feces.  There  is  no  posi- 
tive evidence  that  any  purin  bodies  are  excreted  into  the  feces. 

The  Metabolism  of  the  Individual  Purin  Bodies  in  the  Organism. 
Hypoxanthin.  —  We  have  seen  that  experiments  by  Nencki 
and  Sieber,^  Kriiger  and  Salomon,®  Baginsky,^  and  Jaffe,^  who 
attempted  to  obtain  increased  excretion  of  uric  acid  by  feed- 
ing hypoxanthin,  gave  negative  results.     To  be  sure,  Strauss^ 

1  Bernard  et  Barreswill.     Arch,  de  Mi^decine  (4e  ser.),  t.  13,  p.  449  (1847). 

^E.  Burian  und  H.  Schur.  tjber  die  Stellung  der  Purinkorper  im  menschUchen  Stoff- 
wechsel.     Pfliiger's  Archiv,  II.  Mitteilung  87,  239  (1901). 

3  A  Schittenhelm.  Die  Nucleinbasen  der  Fseces  unter  dem  einfluss  a'nhaltenden  Faul- 
nis.     Zeitschr.  fur  physiol.  Chem.,  39,  199  (1903). 

*  A.  Schittenhelm  und  F.  Schroter.  Ueber  die  Spalting  der  Hefenucleinsaure  durch 
Bakterien.     Zeitschr.  fur  physiol.  Chem.,  39,  203  (1903). 

5  M.  Nencki  und  N.  Sieber.  Ueber  eine  neue  Methode,  die  physiologische  Oxydation 
zu  messen  und  uber  den  Einfluss  der  Gifte  und  Krankheiten  auf  dieselbe.  Pfliiger's 
Archiv,  31,  319  (1883). 

6  M.  Kriiger  und  G.  Salomon.  Die  Konstitution  des  Heteroxanthins  und  seine  physio- 
logische Wirkung.     Zeitschr.  fiir  physiol.  Chem.,  21,  169  (1895). 

^  A.  Baginsky.  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxanthin. 
Zeitschr.  fiir  physiol.  Chem.,  8,  395  (1883). 

8  Jaff^  (cited  by  W.  v.  Mach.  Ueber  die  Bildung  der  Harnsaure  aus  dem  Hypoxanthin. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  24,  389  [1888]). 

9  H.  Strauss.  Ueber  die  Beeinflussung  der  Harnsaure  und  AUoxurkorperausscheidung 
durch  die  Extraktstoff  des  Fleisches.     Berl.  klin.  Wochenschrift,  33,  710  (1896). 


Physiology  155 

had  attributed  the  increased  excretion  of  uric  acid  after  eating 
meat  and  meat  extract  to  hypoxanthin.  But  Minkowski  ^  was 
the  first  to  obtain  positive  results  by  feeding  the  free  base.  In 
dogs  he  found  about  4  per  cent,  and  in  men  about  half  the  hypo- 
xanthin given  excreted  as  uric  acid.  He  found,  however,  an 
increase  in  the  allantoin  in  the  dogs  equivalent  to  77  per  cent 
of  the  hypoxanthin  given.  This  probably  explains  the  origin 
of  the  allantoin  observed  by  Meissner  ^  in  the  urine  of  dogs  and 
cats  after  meat  eating. 

Burian  and  Schur  ^  then  took  up  the  work.  These  authors 
found  that  about  half  the  hypoxanthin  administered  is  excreted 
as  uric  acid,  whether  free  or  combined,  as  it  is  sometimes  found  in 
foodstuffs.  They  give  the  following  list  of  their  own  experiments 
and  the  experiments  of  others.*  The  first  column  gives  the  name 
of  the  experimenter,  the  second  the  food  given,  and  the  third 
shows  what  per  cent  of  the  hypoxanthin  in  the  food  was  excreted 
as  uric  acid.  Galdi^  likewise  found  that  about  one  half  the 
free  hypoxanthin  administered  appears  in  the  urine  as  uric  acid. 

Minkowski/ 
Burian  and  Schur/ 
Krtiger  and  Schmidt/ 
Burian  and  Schur,^ 

))  >>        >> 

Hall,' 

Kaufman  and  Mohr,^ 


hypoxanthin, 

48.6 

yj 

46.2 

yj 

62.3 

beef, 

51.1 

veal, 

53.9 

ham, 

63.2 

chicken. 

52.1 

fish, 

58.2 

beef. 

47.0 

veal. 

51.6 

beef, 

48.1 

85.3 

77.0 

1  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

-  G.  Meissner.  Beitrage  zur  Kenntnis  des  Stoffwechsels  im  thierischen  Organismus. 
Zeitschr.  fiir  rationnelle  Med.,  31,  234  (1868). 

2  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     I.  Mitteilung.     Pfluger's   Archiv.,   80,    241    (1900). 

*  Ihid.  Das  quantitative  Verhalten  der  menschhchen  harnpurinausscheidung.  Pfluger's 
Archiv,  94,  273  (1903). 

5  F.  Galdi.  Ueber  die  Alloxurkorper  im  Stoffwechsel,  bei  Leukamie.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  49,  213  (1903). 

*  M.  Kriiger  und  J.  Schmidt.  Ueber  die  Entstehung  der  Harnsaure  aus  freien  Purin- 
basen.     Zeitschr.  fiir  physiol.  Chem.,  34,  649  (1902). 

^  I.  HaU.  The  Purin  Bodies  of  Food  Stuffs.  Inaug.  Dissert.,  Owens  College,  Man- 
chester, Eng.,  1902. 

Ihid.  The  Relation  of  Purin  Bodies  to  Certain  Metabolic  Disorders.  Brit.  Med.  Journ., 
June  14,  1902. 

*  M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologie  der 
Gicht.     Deutsche  Arch,  fiir  kUn.  Medizin,  74,  141  (1902). 


156      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Burian  and  Schur  think  that  the  individuahty  plays  no  part 
in  determining  the  amount  of  purin  bodies  of  the  food  which  are 
excreted  as  uric  acid  in  the  organism.  The  variations  found  in 
the  different  experiments  are  so  slight  that  they  can  be  due  to 
slight  errors.  The  results  of  the  last  two  experiments  in  the 
table,  they  think,  are  due  to  some  unexplained  error.  In  fact, 
the  patients  used  were  sick. 

Kriiger  and  Schmidt  ^  and  Kaufmann  and  Mohr  ^  think  the 
variations  in  the  results  of  the  different  experiments  indicate 
individual  variations  in  the  amount  of  exogenous  hypoxanthin 
changed  to  uric  acid. 

Burian  and  Schur  ^  found  that  in  different  animals  the  amount 
of  uric  acid  derived  from  a  definite  amount  of  hypoxanthin  is 
diferent.  In  one  race  of.  dogs,  for  example,  he  found  12  per  cent 
of  the  hypoxanthin  injected  excreted  as  uric  acid,  in  another 
race,  only  4  per  cent.  In  rabbits,  about  18  per  cent  of  the  hypo- 
xanthin injected  appears  as  uric  acid.  In  cats  about  one  twen- 
tieth to  one  thirtieth  of  the  uric  acid  injected  is  excreted  as  uric  acid. 

Xanthin.  —  Nencki  and  Sieber  "*  could  not  observe  an  increased 
excretion  of  uric  acid  after  feeding  the  free  base  xanthin  to  dogs. 
Kriiger  and  Salomon  ^  likewise  obtained  negative  results  on  feed- 
ing xanthin  to  rabbits.  Burian  and  Schur  ^  performed  one  ex- 
periment on  man  and  found  an  increased  excretion  of  uric  acid 
corresponding  to  about  30  per  cent  of  the  xanthin  fed.  On  ana- 
lyzing the  feces  they  found  xanthin  present,  which  they  supposed 
was  due  to  lack  of  absorption.  After  subtracting  this  from  the 
amount  given  in  the  food,  they  found  that  the  uric  acid  in  the 
urine  corresponded  to  about  43.5  per  cent  of  the  xanthin  absorbed. 
They  found,  too,  that  of  the  combined  hypoxanthin  and  xanthin 
in  the  liver,  about  52  per  cent  was  excreted  as  uric  acid  in  the 

1  M.  Kriiger  und  J.  Schmidt.  Ueber  die  Entstehung  der  Harnsaure  aus  freien  Purin- 
basen.     Zeitschr.  fiir  physiol.  Chem.,  34,  549  (1902). 

^  M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  AUoxurkorperfrage  und  zur  Pathologic  der 
Gicht.     Deutsche  Arch,  fiir  klin.  Medizin,  74,  141  (1902). 

3  Burian  and  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoffwechsel. 
II.  Mitteilung.     Pfiuger's  Archiv,  87,  239  (1901). 

*  M.  Nencki  und  N.  Sieber.  Ueber  eine  neue  Methode,  die  physiologische  Oxydation  zu 
messen  und  iiber  den  Einfluss  der  Gifte  und  Krankheiten  auf  dieselbe.  Pfliiger's  Archiv, 
31,  319  (1883). 

*  A.  Salomon.  Ueber  das  Vorkommen  von  Xantliin,  und  Hypoxanthin.  Zeitschr. 
fiir  physiol.  Chem.,  8,  395  (1883). 

^  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     I.  Mitteilung.     Pfluger's  Archiv,  80,  241  (1900). 


Physiology  157 

urine.  Burian  and  Schur  concluded  that  xanthin  acts  quanti- 
tatively like  hypoxanthin,  that  is  to  say,  of  the  xanthin  adminis- 
tered, whether  free  or  combined,  about  half  appears  in  the  urine 
as  uric  acid.  Kriiger  and  Schmidt,^  however,  found  in  an  experi- 
ment on  a  man  that  only  10  per  cent  of  the  uric  acid  administered 
appeared  in  the  urine  as  uric  acid. 

Adenin.  — A  great  many  authors,  as  we  have  seen,  have  shown 
that  nucleoproteid  containing  adenin,  for  example,  thymus 
nucleoproteid,  brings  about  increased  excretion  of  uric  acid  when 
fed  to  an  animal.  Burian  and  Schur  ^  showed  that  when  thymus 
is  taken  as  food,  from  22  to  28  per  cent  of  the  adenin  in  its  nucleo- 
proteid is  excreted  as  uric  acid.  Thymus  nucleic  acid  (adenylic 
acid)  also  increases  the  excretion  of  uric  acid  in  dogs,  according 
to  Minkowski^  and  Schittenhelm.* 

After  feeding  the  free  base  adenin  to  dogs,  however,  Minkow- 
ski ^  did  not  find  an  increased  excretion  of  uric  acid  or  of  the 
purin  bases  in  the  urine.  The  adenin  brought  about  inflammation 
of  the  walls  of  the  intestine,  vomiting,  albuminuria,  casts,  and 
leucocytes  in  the  urine  and  crystalline  concretions  in  the  kidneys. 
These  crystalline  concretions  had  the  microscopic  appearance  and 
gave  the  chemical  tests  for  uric  acid.  They  had  the  same  micro- 
scopical appearance  as  those  observed  in  the  kidney  by  Heidenham,^ 
Damsch,^  Ebstein  and  Nicolaier.^  Nicolaier  ^  gave  subcutaneous 
injections  of  adenin  to  rats  and  obtained  concretions  in  their  kid- 
neys identical  with  those  obtained  by  Minkowski.  He  noticed, 
however,  that,  unlike  uric  acid  crystals,  these  crj^stals  dissolve  in 
hydrochloric  acid.  By  quantitative  analysis  Nicolaier  showed  in 
fact  that  these  crystals  are  6-amino-2-8-dioxypurin  or  dioxyadenin. 

1  M.  Kriiger  und  J.  Schmidt.  Ueber  die  Entstehung  der  Harnsaure  aus  freien  Purin. 
basen.     Zeitschr.  fur  physiol.  Chem.,  34,  549  (1902). 

-  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     Pfliiger's  Archiv,  80,  241  (1900). 

3  O.  Minkowski.  Untersuchungen  zur  Pathologie  der  Harnsaure  bei  Saugethieren. 
Arch,  fur  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

^  A.  Schittenhelm  und  E.  Bendix.  Ueber  das  Schicksal  der  in  der  Blutbahn  einge- 
brachten  Nukleinsaure.     Deutsche  med.  Wochenschrift,  30,  1164  (1904). 

5  R.  Heidenham.  Versuche  iiber  den  Vorgang  der  Harnabsonderung.  Pfliiger's 
Archiv,  9,  23  (1874). 

^  Ebstein.     Natur  und  Behandlung  der  Gicht,  78.     Wiesbaden,  1882. 

Ihid.     Natur  und  Behandlung  der  Harnsteine,  77.     Wiesbaden,  1884. 

'Ebstein  und  Nicolaier.  Ueber  die  Ausscheidung  der  Harnsaure  durch  die 
Nieren.     Virchow's  Archiv,  143,  337  (1898). 

*  Nicolaier.  Ueber  die  Umwandlung  des  Adenins  im  Thierischen  Organismus.  Zeitschr. 
fiir  khn.  Medizin,  45,  359  (1902). 


158     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 


N  =  CNH2 

N  = 

=  CNH^ 

NH- 

-CO 

CH   C  — NH\ 

II          II                  \  riTT 

II        II              ^CH 

N— C  —  N  ^ 

CO 

C  — NH\ 

II           )co 
-c  — nh/ 

CO 
NH- 

C  — NH\ 
II               /CO 
-C  — NH/ 

adenin 

dioxyadenin 

uric  acid 

Schittenhelm  ^  found  that  small  doses  of  adenin  have  no  effect 
on  rabbits.  After  large  doses,  concretions  similar  to  those 
found  in  dogs  are  found  in  the  kidneys.  In  neither  case  is  there 
an  increase  in  the  excretion  of  uric  acid.  Kriiger  and  Schmidt^ 
found  that  if  the  free  base  adenin  be  fed  to  man,  about  41  per 
cent  is  oxidized  and  excreted  as  uric  acid.  This  is  a  larger  fraction 
even  than  that  obtained  by  Burian  and  Schur  from  the  adenin 
combined  in  thymus.  We  see  that  adenin,  like  hypoxanthin,  acts 
differently  in  different  mammals.  Kriiger^  has  since  shown  that 
this  increased  excretion  of  uric  acid  is  real  and  not  due  to  an  increase 
in  the  quantity  of  chemically  similar  6-amino-2-6-dioxypurin,  as 
had  been  suggested.  Thus,  while  thymus  feeding  increases  the 
excretion  of  uric  acid  in  man,  Cohn,^  Minkowski,-^  and  Burian  and 
Schur®  observed  very  little  increased  excretion  of  uric  acid  in  dogs, 
and  Mendel  and  Brown  ^  in  cats,  but  a  very  marked  increase  in  the 
excretion  of  allantoin,  which  is  a  decomposition  product  of  uric  acid. 

GuANiN.  —  Weiss,^  Hess  and  Schmoll,^  and  Loewi^'^  observed 
increased  uric  acid  excretion  in  man  after  pancreas  feeding. 
Experiments  with  the  free  base  guanin,  which  is  the  purin  base 

1  A.  Schittenhelm.  Das  Verhalten  von  Adenin  und  Guanin  im  tierischen  Organismus. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  47,  432  (1902). 

2  M.  Kriiger  und  J.  Schmidt.  Ueber  die  Entstehung  der  Harnsaure  aus  freien  Puiin- 
basen.     Zeitschr.  fur  physiol.  Chem.,  34,  549  (1902). 

3  M.  Kriiger.  Ueber  die  Umwandlung  der  Purinkorper  im  Organismus.  Deutsche  med. 
Wochensohrift,  29,  741  (1903). 

■*  T.  Cohn.  Beitrage  zur  Kenntniss  des  Stoffwechsels  nach  Thymusnahrung. 
Zeitschr.  fur  physiol.  Chem.,  25,  507  (1898). 

5  O.  Minkowski.  Untersuchungen  zur  Physiol  ogie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

8  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschhchen  Stoff- 
wechsel.     II.  Mitteilung.     Pfiiiger's  Archiv,  87,  239  (1901). 

'  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the  Cat, 
Especially  on  the  Excretion  of  Uric  Acid  and  Allantoin.  Am.  Journ.  of  Physiol.,  3,  261 
(1900). 

*  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fiir  physiol.  Chem.,  27,  216  (1899). 

8  N.  Hess  und  E.  SchmoU.  Ueber  die  Beziehungen  der  Eiweiss  und  Paranukleinsub- 
stanzen  der  Nahrung  zur  AUoxurkorperausscheidung  im  Harne.  Arch,  fiir  exp.  Path, 
u.  Pharmak.,  37,  243  (1896). 

1°  Loewi.  Untersuchungen  iiber  den  Nukleinstoffwechsel.  II.  Mitteilung.  Arch,  fur 
exp.  Path.  u.  Pharmak.,  45,  157  (1901). 


Physiology  159 

of  pancreas  nucleoproteid,  on  rabbits  by  Kerner/  on  dogs  by 
Stadthagen,^  and  on  man  by  Burian  and  Schur  ^  and  Milroy  and 
Malcolm  ^  gave  negative  results.  In  dogs,  vSalkowski^  found  in- 
creased allantoin  after  pancreas  feeding  instead  of  increased  uric 
acid.  Mendel  and  Brown^  observed  the  same  effect  in  cats,  although 
there  was  likewise  a  shghtly  increased  excretion  of  uric  acid. 
Schittenhelm  ^  found  no  increased  uric  acid  after  feeding  guanin 
to  rabbits,  and  found  no  concretions  in  the  kidneys  such  as  were 
noticed  after  adenin  feeding.  He  found,  however,  that  the  uric  acid 
excretion  was  increased  when  the  guanin  was  introduced  subcutane- 
ously  or  intravenously.^  Kriiger  and  Schmidt  ^  performed  one  ex- 
periment on  a  man  in  which  a  very  small  amount  of  free  guanin  was 
given.     A  very  slightly  increased  excretion  of  uric  acid  was  noticed. 

According  to  Hall,^''  guanin  is  poorly  absorbed.  Fifty  per  cent 
of  the  guanin  fed  is  found  again  in  the  feces. 

Before  leaving  the  subject  of  the  influence  of  these  four  bases 
on  the  excretion  of  uric  acid,  it  may  be  well  to  state  by  way  of 
summary  that  although  the  oxidation  of  hypoxanthin  and  the 
hypoxanthin  in  nuclein  and  nucleoproteid  is  to  some  extent 
clear,  yet  the  results  obtained  by  a  study  of  the  metabolism  of 
the  other  three  bases,  xanthin,  adenin,  and  guanin,  by  different 
authors  are  contradictory.  It  has  not  even  been  decided 
conclusively  whether  it  makes  a  difference  if  the  bases  are 
administered  free  or  combined  in  nucleoproteid.  A  few  more 
experiments  ought  to  clear  up  the  subject.  It  seems  clear  that 
the  metabolism  of  these  bases  is  different  in  different  mammals. 

1  A.  Kerner.  Ueber  das  Verhalten  des  Guanins.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
103,  249  (1857). 

2  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaiire  in  verscheidenen  thierischen  Or- 
ganen,  ihr  Verhalten  bei  der  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  StickstoS- 
basen.     Virchow's  Archiv,  109,  390  (1887). 

5  Burian  und  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoffwechsel. 
I.  Mitteilung.     Pfliiger's  Archiv,  80,  241  (1900). 

*  T.  Milroy  and  J.  Malcolm.  The  Metabolism  of  the  Nucleins  under  Physiological  and 
Pathological  Conditions.     Journ.  of  Physiol.,  23,  217  (1899). 

5  E.  Salkowski.  Ueber  das  Vorkommen  von  Allantoin  im  Ham  nach  Fiitterung  mit 
Pankreas.     Centralbl.  fiir  med.  Wissensohaften,  36,  929  (1898). 

8  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the  Cat, 
Especially  on  the  Excretion  of  Uric  Acid  and  Allantoin.  Am.  Journ.  of  Physiol., 
3,  261  (1900). 

'  A.  Schittenhelm.  Das  Verhalten  von  Adenin  und  Guanin  im  tierschen  Organismus. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  47,  432  (1902). 

*  A.  Schittenhelm  und  E.  Bendix.  Um  die  Umwandlung  des  Guanins  im  Organismus 
des  Kaninchens.     Zeitschr.  fiir  physiol.  Chem.,  43,  365  (1905). 

'  Kriiger  und  Schmidt.  Ueber  die  Entstehung  der  Harnsaure  aus  freien  Purinbasen. 
Zeitschr.  fur  physiol.  Chem.,  34,  549  (1902). 

i"!.  HaU.     The  Purin  Bodies  of  Food  Stuffs.     Second  ed.  Manchester,  Eng.,  1903. 


160      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Uric  Acid. — Frerichs  and  Wohler  ^  foubd  no  increased  excre- 
tion of  uric  acid  in  rabbits  after  ingestion  of  urates,  or  in  dogs  by 
feeding  them  uric  acid.  Neubauer  ^  found  that  the  uric  acid 
given  to  rabbits  is  excreted  as  urea.  Zabehn^  and  Meissner,*  who 
tried  experiments  on  dogs,  and  Mendel  and  Brown,'^  who  used 
cats,  found  that  the  uric  acid  ingested  is  not  excreted  as  such. 
Burian  and  Schur,''  however,  observed  in  dogs  and  cats  that  about 
one  twentieth  to  one  thirtieth  of  the  uric  acid  ingested  is  excreted 
unchanged.  Thus,  in  dogs  and  cats,  hypoxanthin,  the  adenin 
in  thymus,  and  uric  acid,  in  equal  doses,  give  the  same  quantity 
of  uric  acid  in  the  urine.  Poduschka^  noticed  a  very  slight  in- 
crease in  the  excretion  of  uric  acid  by  dogs  after  ingestion  of 
sodium  urate. 

In  man  the  conclusions  are  slightly  different.  After  eating 
7.5  grams  uric  acid  in  one  day,  Stokvis  ^  observed  no  increase 
in  the  excretion  of  uric  acid.  Stadthagen "  ate  5  grams  sodium 
urate  and  found  that  apparently  none  of  it  appeared  again  as 
such  in  the  urine.  The  fact  that  uric  acid  administered  per  os 
does  not  reappear  in  the  urine  has  been  confirmed  by  Wein- 
traud,^"  Weiss,"  Schreiber  and  Waldvogel,^^  and  Loewi.^^     Only 

1  r.  Frerichs  und  F.  Wohler.  Ueber  die  Veranderungen,  welche  namentlich  organische 
Stoffe  bei  ihrem  Ubergang  in  den  Harn  erleiden.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
65,  335   (1848). 

^  C.  Neubauer.  Ueber  die  Zersetzung  der  Harnsaure  im  Tierkorper.  Liebig's  Ann. 
d,er  Chem.  u.  Pharm.,  99,  206  (1856). 

3  Zabelin.  Ueber  die  Umwandlung  der  Harnsaure  im  Thierkorper.  Liebig's  Ann. 
der  Chem.  u.  Pharm.,  Suppl.,  2,  326  (1863). 

*  G.  Meissner.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  tierischen  Organismus. 
Zeitschr.  fur  rationeUe  Med.,  III.  Reihe,  31,  234  (1868). 

^  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the  Cat. 
Especially  on  the  Excretion  of  Uric  Acid  and  AUantoin.  Am.  Journ.  of  Physiol.,  3,  261 
(1900). 

8  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschUchen  Stofi- 
wechsel.     2.  Mitteilung.     Pfluger's  Archiv,  87,  239  (1901). 

^  Poduschka.  Quantitative  Versuche  iiber  Allantoinausscheidung.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  44,  59  (1900). 

8  Stokvis.     Arch.  f.  d.  holl.  Beitrage  2,  Serie  2,  260  (1860).     Cited  by  Burian  and  Schur. 

^  Stadthagen.  Ueber  das  Vorkommen  des  Harnsaure  in  verscheidenen  thierischen 
Organen,  ihr  Verhalten  bei  Leukamie,  und  die  Frage  ihrer  Entstehung  aus  den  Stickstoff- 
basen.     Virchow's  Archiv,  109,  390  (1887). 

'"  Weintraud.  Ueber  Harnsaure  im  Blute  und  ihre  Bedeutung  fiir  die  Entstehung  der 
Gicht.  Centralblatt  fur  innere  Medizin,  17,  752  (1896),  and  Wiener  klin.  Rundschau,  1896, 
Nos.  1  and  2. 

1^  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fur  physiol.  Chem.,  27,  216  (1899). 

^^  Schreiber  und  Waldvogel.  Beitrage  zur  Kenntnis  der  Harnsaureausscheidung  unter 
physiologischen  und  pathologischen  Verhaltnissen.  Arch,  fiir  exp.  Path.  u.  Pharmak., 
42,  69  (1899). 

^^  O.  Loewi.  Beitrage  zur  Kenntnis  des  Nukleinstoffwechsel.  1.  Mitteilung.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  44,  1  (1901). 


Physiology  161 

Donogany  ^  and  Haig  -  'find  that  administration  of  uric  acid  per 
OS  in  man  gives  increased  excretion  of  uric  acid. 

Burian  and  Schur  ^  have  found  that  about  48  per  cent  of  the 
uric  acid  injected  subcutaneously  into  a  man  reappears  un- 
changed in  the  urine.  About  the  same  fraction  of  the  hypo- 
xanthin  eaten  is  excreted  as  uric  acid.  Soetbeer  and  Ibrahim  * 
found  that  uric  acid  taken  into  the  stomach  does  not  increase  the 
excretion  of  uric  acid,  probably,  according  to  them,  because  it 
is  only  slightly  absorbed,  but  found  that  uric  acid  administered 
by  intravenous  injection  appears  almost  quantitatively  in  the 
urine.  Soetbeer  and  Ibrahim  performed  but  two  experiments 
to  deterinine  the  effect  of  uric  acid  injections.  During  the  second 
experiment  the  patient  became  sick,  so  that  the  quantitative 
conclusions  which  they  drew  are  not  above  criticism.  The  work 
of  His,^  Freud weiler,*^  and  Ebstein  and  Nicolaier^  has  some  bear- 
ing on  this  point.  These  authors  found  that  when  uric  acid  is 
injected  into  rabbits  and  men  it  causes  inflammation,  precipitates 
out  to  some  extent,  and  is  not  fully  absorbed  for  some  time. 

Weintraud  ^  suggested  that  the  reason  that  uric  acid  corre- 
sponding to  only  a  part  of  the  purin  bases  in  the  food  appears 
in  the  urine  is  that  a  certain  fraction  of  the  bases  is  oxidized 
directly  to  urea.  Only  that  part  of  the  bases  which  reaches 
the  place  in  the  body  where  an  oxidation  to  uric  acid  takes  place 
is  changed  to  uric  acid.  According  to  Burian  and  Schur,^  how- 
ever, about  one  half  of  the  hypoxanthin  or  xanthin  administered 
appears  as  uric  acid  in  the  urine,  and  about  one  half  of  the  uric 

1  Donogany.  Ueber  Ausnutzung  einige  Nahrungs  im  Darmkanal.  Zeitschr.  fur  Biol., 
15,  115,  and  Rubner.     Lehrb.  d.  Hygiene  V.  Aufl.,  p.  532. 

2  A.  Haig.  Does  Uric  Acid  Taken  by  Mouth  increase  the  Excretion  of  that  Substance 
in  the  Urine?     Joum.  of  Physiol.,  15,  167  (1894). 

3  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     2.  Mitteilung.     Pfliiger's  Archiv,  87,  239  (1901). 

4  F.  Soetbeer  und  J.  Ibrahim.  Ueber  das  Schicksal  eingefiihrter  Harnsaure  im  mensch- 
lichen organismus.     Zeitschr.  fiir  physiol.  Chem.,  35,  1  (1902). 

5  W.  His.  Schicksal  und  Wirkungen  des  sauren  harnsauren  Natrons  in  Bauch-  und 
Gelenkhohle  des  Kaninchens.     Deutsche  Arch,  fiir  klin.  Medizin,  67,  81  (1900). 

^  M.  Freudweiler.  Experimentelle  Untersuchungen  iiber  das  Wesen  der  Gichtknoten. 
Deutsche  Arch,  fiir  klin.  Medizin,  63,  266  (1899). 

'  W.  Ebstein  und  A.  Nicolaier.  Ueber  die  Ausscheidung  der  Harnsaure  durch  die 
Nieren.     Virchow's  Archiv,  147,  337  (1896). 

8  W.  Weintraud.  Ueber  die  Einfluss  des  Nukleins  der  Nahrung  auf  die  Harnsaure- 
ausscheidung.     Berl.  kUn.  Wochenschrift,  32,  405  (1895). 

Ibid.  Ueber  Harnsaurebildung  beim  Menschen.  Vortrag  gehalten  in  der  physiol. 
Gesellsch.  zu.  Berl.  am  1  Marz,  1895.     DuBois  Archiv,  382  (1895). 

Ihid.  Ueber  Harnsaure  im  Blute  und  ihre  Bedeutung  fiir  die  Entstehung  der  Gicht. 
Wiener  klin.  Rundschau,  No.  1,  1896,  und  Centralblatt  fiir  innere  Medizin,  17,  752  (1896). 


162      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

acid  injected  appears  unchanged  in  the  urine.  This  would  seem 
to  indicate  that  hypoxanthin  and  xanthin  are  oxidized  almost 
wholly  to  uric  acid,  and  then  about  half  this  uric  acid  is  destroyed. 
In  the  case  of  adenin,  where  only  about  a  fourth  appears  as  uric 
acid  in  the  urine,  it  seems  probable  that  only  one  half  the  adenin 
is  changed  to  uric  acid. 

We  can  see,  then,  that  in  regard  to  the  behavior  of  the  oxy- 
and  amino-purins  in  the  organism  there  is  much  yet  to  learn. 
We  know  that  in  man  the  uric  acid  excreted  comes  from  two 
sources,  —  the  body  tissue  and  the  nucleoproteid  and  purin  bases 
of  the  food.  The  amount  which  comes  from  the  body  tissue  is 
different  for  different  individuals,  but  approximately  constant 
for  the  same  individual  at  different  times  under  like  conditions. 
Of  the  hypoxanthin  administered,  whether  free  or  combined  in 
nucleoproteid,  about  one  half  is  excreted  as  uric  acid.  Further 
experiment  is  needed  before  we  can  state  with  certainty  how 
much  of  the  xanthin,  adenin,  and  guanin  administered  is  excreted 
as  uric  acid.  It  is  not  certain,  either,  whether  or  not  it  makes 
a  difference  if  the  adenin  and  guanin  are  free  or  combined,  as  in 
nucleoproteid.  Perhaps  there  is  a  difference  in  the  absorption. 
The  work  of  Burian  and  Schur  seems  to  indicate  that  a  large  part 
of  the  uric  acid  injected  intravenously  is  excreted  unchanged. 
Numerous  experiments  show  that  uric  acid  administered  by  the 
mouth  is  destroyed  in  the  organisms,  if  we  assume  that  it  is  ab- 
sorbed, but  this  is  an  unproved  assumption.  In  dogs,  cats,  and 
rabbits  a  much  smaller  part  of  the  oxy-  and  amino-purins  admin- 
istered appears  in  the  urine  as  uric  acid  than  in  man.  In  dogs  and 
cats  the  uric  acid  is  apparently  further  oxidized  to  allantoin. 

The  Methyl  Purins.  —  The  influence  of  caff'ein  and  theobromin 
on  the  excretion  of  uric  acid  is  of  importance  on  account  of  the 
occurrence  of  caffein  in  coffee  and  tea  and  the  occurrence  of  theo- 
bromin in  cocoa. 

Caffein  {l-3-7-Trimethyl-2-Q-Dioxypurin).  — 

CH3  — N  — CO 

I         I  /  CH3 

CO    C  — N^ 

CH,  — N  — C  — N^*^^ 


Physiology  163 

Before  the  relation  of  caffein  to  the  other  piirin  bodies  was 
understood,  practically  nothing  was  known  concerning  its  meta- 
bolism in  the  body.  Neither  Lehmann^  nor  Hammersten^  found 
caffein  in  the  urine  after  giving  it  in  the  food.  Aubert^  found 
caffein  in  the  urine  after  coffee  drinking.  Schutzenkwer*  ob- 
tained a  qualitative  test  for  caffein  in  the  urine  of  dogs  after  feed- 
ing 4.8  grams  of  caffein  to  them.  Maly  and  Andreasch;^  after 
administration  of  .1  gram  of  caffein,  found  66  per  cent  of  it  un- 
changed in  the  urine.  Rost"  found  from  1  to  8  per  cent  of  the 
caffein  administered  unchanged  in  the  urine.  Albanese  ^  found 
only  traces  of  caffein  in  the  urine  of  dogs  fed  with  caffein  for  a 
month.  He  found  considerable  quantities  of  a  monomethyl- 
xanthin.  Bondzynski  and  Gottlieb^  found  a  methylxanthin  in 
the  urine  after  feeding  caffein  to  dogs,  which  they  later^  identi- 
fied as  heteroxanthin  (7-methylxanthin).  Albanese^"  has  since 
shown  that  the  monomethylxanthin  found  in  dogs'  urine  after 
caffein  is  not  heteroxanthin,  but  3-methylxanthin. 

In  rabbits,  Schutzenkwer*  found  after  administration  of  .2  gram 
caffein,  6  per  cent  unchanged  in  the  urine.  Rost^  found  from 
11  to  21  per  cent  unchanged  in  the  urine.  Bondzynski  and  Gott- 
lieb ^^  found  a  monomethylxantliin  in  the  urine  after  feeding 
caffein  to  rabbits,  which  they  later  identified  as  heteroxanthin 
7-methylxanthin. 

Albanese^  found  in  the  urine  after  feeding  caffein  to  rabbits  a 
little  unchanged  caffein,  a  little  xanthin,  but  no  monomethyl- 

1  Lehmann.     Lehrbuch  der  physiol.  Chem.,  vol  2,  367  (1850). 

2  Hanunersten.     N.  Jahrb.  Pharm.,  xxxv  (1871). 

3  H.  Aubert.  Ueber  Coffeingehalt  des  Kaffeegetrankes  und  uber  die  Wirkungen  des 
Coffeins.     Pfliiger's  Archiv,  5,  589  (1872). 

*  Schutzenkwer.  Das  Coffein  und  sein  Verhalten  im  Thierkorper.  Inaug.  Dissert., 
Konigsberg  (1882). 

5  Maly  und  Andreaseh.  Studien  iiber  Coffein  und  Theobromin.  Monatshefte  fiir 
Chemie.  iv,  393  (1883). 

6  Rost.  Ueber  die  Ausscheidung  des  Coffeins  und  der  Theobromins  in  der  Harn.  Arch, 
fur  exp.  Path.  u.  Pharmak.,  36,  56  (1895). 

'  M.  Albanese.  Ueber  das  Verhalten  des  Caffeins  und  des  Theobromins  im  Organismus. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  35,  449  (1895). 

8  S.  Bondzynski  und  R.  Gottlieb.  Ueber  Methylxanthin  ein  Stoffwechselprodukt  des 
Theobromins  und  Coffeins.  Arch.  fiir.  exp.  Path.  u.  Pharmak.,  36,  451(1895),  und  Ber 
der  Dtsch.  chem.  Gesell.,  28,  1113  (1895). 

^  Ihid.  Ueber  die  konstitution  der  nach  Caffeins  und  Theobromin  im  Harne  auftre- 
tenden  Methylxanthins.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  37,  385    (1896). 

1"  M.  Albanese.  Ueber  die  BUdung  von  3-MethyLxanthin  aus  Coffeinlim  thierischen 
Organismus.     Ber.  der.  Dtsch.  chem.  Gesell.,  32,  2280  (1899). 

"  S.  Bondzynski  und  R.  Gottlieb.  Ueber  Methylxanthin  ein  Stoffwechselprodukt  des 
Theobromins  und  Coffeins.     Arch,  fur  exp.  Path.  u.  Pharmak,  36,  45  (1895). 

Ibid.     Ber.  der/Dtsch.  chem.  Gesell.,  28,  1113  (1895). 


164      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

xanthin.  Kriiger  ^  found  in  rabbits'  urine  after  feeding  caffein 
1-7-dimethylxanthin,  1-methylxanthin,  and  7-methylxanthin, 
but  only  a  trace  of  3-methylxanthin. 

In  cats,  according  to  Schneider,^  the  greater  part  of  the  caffein 
administered  is  destroyed.  According  to  Rost,^  from  traces  up 
to  2.4  per  cent  of  the  amount  of  caffein  administered  is  excreted 
unchanged  in  cats. 

In  men,  no  caffein  could  be  found  in  the  urine  after  coffee 
drinking  by  Dragendorff,*  or  after  caffein  eating  by  Schneider.^ 
Rost^  found  only  about  ^  per  cent  of  the  caffein  administered 
unchanged  in  the  urine.  Albanese  ^  found  xanthin  in  human 
urine  after  use  of  tea  and  coffee  in  the  food,  but  no  caffein  or 
monomethylxanthin.  After  caffein  feeding  he  obtained  dimethyl- 
xanthin  and  some  caffein  in  the  urine. 

Theohromin  {{i-7-Dimethylxanthin).  — 

NH  — CO 

I  I         /CH3 

CO       C  — N\ 
I  li  )CH 

CH3  — N  —   C— N^ 

Lehm.ann  ^  found  that  theobromin  administered  does  not  reap- 
pear in  the  urine,  but  did  not  specify  upon  what  animal  the 
experiments  were  performed.  Rost^  found  that  from  10  to 
32  per  cent  of  the  theobromin  administered  to  dogs  reappears 
in  the  urine.  Bondzynski  and  Gottlieb^  found  monomethyl- 
xanthin in  dogs'  urine  after  administration  of  theobromin. 
Albanese'^  found  2  grams  of  monomethylxanthin  in  dogs'  urine 
after  administration  of  10  grams  in  the  food.  Kriiger  and 
Schmidt^  found  after  administration  of  100  grams  theobromin, 

1  M.  Kriiger.  Ueber  den  Abban  des  Caffeins  im  Organismus  des  Kaninchens.  Ber. 
der  Dtsch.  chem.  Gesell.,  32,  3336  (1899). 

2  Schneider.  Ueber  das  Schicksal  des  Caffeins  und  Theobromins  im  Thierkorper. 
Inaug.  Dissert.  Dorpat.  (1884). 

3  Rost.  Ueber  die  Ausscheidung  des  Coffeins  und  der  Theobromins  in  der  Harn.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  36,  56  (1895). 

*  Dragendorff.     Beitrage  zur  gerichtlichen  Chem.,  108  (1871). 

s  M.  Albanese.  Ueber  das  Verhalten  des  Coffeins  und  des  Theobromins  im  Organismus. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  35,  449  (1895). 

^  Lehmann.     Lehrbuch.  der  physiol.  Chem.,  vol.  2,  367  (1850). 

^  S.  Bondzynski  und  R.  Gottlieb.  Ueber  Methylxanthin  ein  Stoffwechselprodukt  der 
Theobromins  und  Caffeins.  Arch,  fiir  exp.  Path.  u.  Pharmak.,  36,  45  (1895),  und  Ber.  der 
Dtsch.  chem.  Gesell.,  28,  1113  (1895). 

*  M.  Kriiger  und  P.  Schmidt.  Ueber  das  Verhalten  von  Theobromin,  Paraxanthin, 
und  3-Methylxanthin  im  Organismus.     Ber.  der  Dtsch.  chem.  Gesell.,  32,  2677  (1899). 


Physiology  165 

51  grams  unchanged  theobromin,  .63  gram  of  7-methylxanthin, 
and  2.9  grams  of  3-methylxantMn  in  the  urine  of  dogs. 

In  rabbits,  Rost^  found  4  to  28  per  cent  of  the  theobromin 
administered  unchanged  again  in  the  urine.  Bondzynski  and 
Gottheb  obtained  monomethylxanthin  after  administration  of 
theobromin  to  rabbits  ,=*  and  found  19  per  cent  of  the  theobromin 
administered  unchanged  in  the  urine,  and  25  per  cent  as  a 
monomethylxanthin.^  Kruger  and  Schmidt*  found  that  of 
100  grams  theobromin  administered  to  rabbits,  16  grams  appeared 
unchanged,  14  grams  as  7-methylxanthin,  and  .9  gram  as  3- 
methylxanthin.  Hofmann^  found  theobromin  in  human  urine 
after  administration  of  diuretin  a  double  salt  of  theobromin  and 
salicylic  acid. 

Rost  found  18  to  20  per  cent  of  the  theobromin  administered 
to  men  unchanged  in  the  urine.  Bondzynski  and  Gottlieb  ^ 
found  a  monomethylxanthin  in  human  urine  after  feeding  theo- 
broinin. 

Other  Methyl  Purins.  —  Kriiger  and  Schmidt''  found  after 
administration  of  theophylhn  (1-3-dimethylxanthin)  to  a  dog, 
17.7  per  cent  unchanged  in  the  urine  and  17.9  per  cent  as 
3-methylxanthin. 

After  administration  of  12  grams  of  paraxanthin  (1-7-dimethyl- 
xanthin)  to  a  rabbit/  these  same  authors  found  .9  gram  in  the 
urine  unchanged,  and  .14  gram  as  1-methylxanthin. 

Minkowski^  found  that  7-methyladenin  is  excreted  in  large 
part  unchanged  when  administered  to  dogs. 

Effect  of  the  Methyl  Purins  on  Uric  Acid  Excretion.  —  In 
dogs,  Schutzenkwer  ^  did  not  observe  any  effect  of  caffein  on 
the  uric  acid  excretion.     This  was  confirmed  by  Minkowski,^  who 

1  Rost.  Ueber  die  Ausscheidung  des  Coffeins  und  der  Theobromins  in  der  Harn.  Arch, 
fur  exp.  Path.  u.  Pharmak.,  36,  56  (1895). 

*S.  Bondzynski  und  R.  Gottheb.  Ueber  Methylxanthin  ein  Stoffwechselprodukt  des 
Theobromins  und  Caffeins.     Ber.  der  Dtsch.  chem.  Gesell.,  28,  1113  (1895). 

3  Ibid.  Methylxanthin  ein  Stoffwechselprodukt  des  Theobromins  und  Caffein.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  36,  45  (1895). 

4  M.  Kruger  und  P.  Schmidt.  Ueber  das  Verhalten  von  Theobromin,  Paraxanthin, 
und  3-Methylxanthin  im  Organismus.     Ber.  der  Dtsch.  chem.  Gesell.,  32,  2677  (1899). 

5  A.  Hofmann.  Ueber  die  therapeutisch  Anwendung  des  Diuretin  (theobromin-natrium- 
natriumsaUcylate).     Arch,  fiir  exp.  Path.  u.  Pharmak.,  28,  1  (1891). 

6  M.  Kruger  und  J.  Schmidt.  Der  Abbau  des  Theophyllins  1-3-Dimethylxanthins  im 
Organismus  des  Hundes.     Zeitschr.  fiir  physiol.  Chem.,  36,  1  (1902). 

7  O.  Minkowski.  Untersuchungen  zur  Physiologic  und  Pathologic  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

8  Schutzenkwer.  Das  Caffein  und  sein  Verhalten  im  Thierkorper.  Inaug.  Dissert., 
Konigsberg  (1882). 


|66      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

observed  likewise  no  increase  in  the  excretion  of  uric  acid  after 
feeding  to  dogs  7-methyladenin.  After  administration  of  9- 
methyladenin,  however,  there  was  a  shght  increase  in  the  excre- 
tion of  uric  acid. 

In  man,  Haig,^  whose  results,  as  we  have  already  seen,  are 
open  to  criticism  on  account  of  the  inaccurate  method  of  deter- 
mination, and  on  account  of  the  fact  that  he  refers  to  the  ratio 
uric  acid  :  urea,  found  increased  uric  acid  after  coffee  drinking. 
Taylor,^  after  coffee  drinking,  and  Hess  and  Schmoll,^  after  tea 
and  cocoa  drinking,  likewise  observed  a  very  slight  increase  in  the 
excretion  of  uric  acid. 

Leven,*  whose  method  of  analysis,  however,  was  inaccurate, 
found  no  effect  of  coffee  on  the  excretion  of  uric  acid.  Zagari 
and  Pace^  found  no  increased  excretion  of  uric  acid,  but  an  in- 
creased excretion  of  purin  bases  after  caffein.  Burian  and  Schur  ® 
found  that  coffee  has  no  effect  on  the  excretion  of  uric  acid.  Of 
the  purin  base  in  coffee,  about  35  to  40  per  cent  appears  as  purin 
bases  again  in  the  urine. 

It  will  be  seen,  then,  that  the  methyl  groups  of  the  methyl- 
purins  are  gradually  oxidized  off  in  the  organism.  The  extent 
to  which  the  methyl  groups  are  removed  from  such  a  compound 
and  the  position  of  the  methyl  group  first  attacked  depends  upon 
the  kind  of  animal  used.  It  would  seem,  a  priori,  that  if  xanthin 
is  formed  by  complete  removal  of  methyl  groups,  this  would 
give  some  uric  acid  on  further  oxidation.  Direct  experiments 
indicate  that  if  there  is  an  increase  in  the  excretion  of  uric  acid 
after  administration  of  methylpurins,  it  is  insignificant  in  amount. 

URIC  ACID  FROM  PROTEID 

As  we  have  seen,  the  early  physiologists  considered  uric  acid 
an  antecedent  of  urea  in  the  destructive  metabolism  of  proteid. 

1  Haig.     Uric  Acid  as  a  Factor  in  Causation  of  Diseases.     London  (1896). 

2  A.  Taylor.  The  Influence  of  Various  Diets  upon  the  EUmination  of  Uric  Acid  and  the 
Purin  Bases.     Amer.  Journ.  of  Med.  Sciences,  118,  141  (1899). 

2  Hess  und  Schmoll.  Ueber  die  Beziehung  der  Eiweiss-  und  Paranukleinsubstanzen 
der  Nahrung  zur  Alloxm-korper  im  Harn.  Arch,  fiir  exp.  Path.  u.  Pharmak.,  37,  243 
(1896). 

*  Leven.  Action  physiologique  et  medicamenteuse  de  la  caffine.  Arch,  de  physiol. 
norm,  et  path.,  t.  1,  p.  179  (1868). 

6  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  all'  indirizzo  terapeutico.     Napoli  (1897). 

6  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     1.  Mitteilung.     Pfliiger's  Archiv,  80,  241  (1900). 


Physiology  167 

Thus,  in  Neubauer's  article,^  and  in  the  old  textbooks  of  Liebig,^ 
Lehmann,^  and  Gorup-Besanez/  we  find  the  presence  of  uric 
acid  in  the  urine  attributed  to  an  incomplete  oxidation  of  proteid. 
This  view  was  based  on  the  ease  with  which  uric  acid  can  be  oxi- 
dized to  urea  outside  the  body,  and  on  the  fact  that  Wohler  and 
Frerichs  ^  found  on  administration  of  uric  acid  to  rabbits  that 
there  was  no  increased  excretion  of  uric  acid,  but  a  very  greatly 
increased  excretion  of  urea.  It  may  be  of  interest  to  state  that 
so  recently  as  1901  Halliburton  °  states  that  a  diminution  of 
oxidation  processes,  such  as  occurs  in  persons  with  sedentary 
habits,  is  one  of  the  two  conditions  which  lead  to  an  increased 
excretion  of  uric  acid. 

An  increased  excretion  of  uric  acid  was  looked  upon  as  an  indi- 
cation of  diminished  oxidation  in  the  organism.  Virchow ' 
found  that  in  leukemia  there  is  an  increased  excretion  of  uric 
acid.  He  believed  that  this  might  be  due  to  an  oxidation  of  the 
hypoxanthin  present  in  the  blood  through  the  increased  activity 
of  the  spleen  in  this  disease,  or  it  might  be  due  to  a  diminished 
oxidation  power  of  the  organism.  He  had  previously  stated^ 
that  in  leukemia  there  is  probably  a  condition  of  diminished 
oxidation  brought  about  by  the  decreased  number  of  red  blood 
corpuscles.  This  would  occasion,  according  to  him,  a  diminished 
internal  respiration,  —  a  decreased  supply  of  oxygen  to  the 
tissues.  In  this  case  there  would  not  be  sufficient  oxygen  present 
to  oxidize  the  proteid  completely  to  urea,  and  a  larger  amount 
than  normally  would  reach  the  stage  only  of  uric  acid. 

As  we  have  already  seen,  a  considerable  number  of  experi- 
menters during  the  next  three  decades  found  the  excretion  of 
uric  acid  in  leukemia  high.  Some  of  them  thought  this  was  due 
to  the  oxidation  of  hypoxanthin  from  the  spleen.  We  have 
seen  how  this  idea  finally  led  up  to  the  present  views  concerning 

1  C.  Neubauer.  Ueber  der  Zersetzung  der  Harnsaure  im  Tierkorper.  Liebig's  Ann. 
der  Chem.  u.  Pharm.,  99,  206  (1856). 

-J.  Liebig.  Animal  Chemistry,  or  Organic  Chemistry  in  its  Application  to  Physiologj' 
and  Pathology.     Transl.  by  W.  Gregory.     (1843)  Ed.  by  J.  Webster,  Cambridge. 

3C.  Lehmann.     Physiologische  Chemie,  Vol.  1,  2d  ed.  (1853). 

^  Gorup-Besanez.     Lehrbuch  der  physiol.  Chemie,  3.  Aufl.,  1874. 

^  F.  Wohler  und  F.  Frerichs.  Ueber  der  Veranderungen,  welche  namentlich  organische 
Stoffe  beim  Uebergang  in  den  Ham  erleiden.  Liebig's  Ann.  der  Chem.  u.  Pharm., 
65,   335    (1848). 

6  Halliburton.     The  Essentials  of  Chemical  Physiology.     London  (1901). 

^  R.  Virchow.  Zur  pathologischen  Physiologie  des  Blutes.  Virchovv'.s  Archiv,  5,  43 
(1853). 

^Ibid.     Virchow's  Archiv,  1,  547  (1847). 


168      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

the  source  of  uric  acid.  Until  Kossel's  work  on  the  nucleins,  how- 
ever, about  thirty  years  ago,  hypoxanthin  was  looked  upon  as  a 
decomposition  product  of  proteid,  so  that  in  any  case  the  ultimate 
physiological  source  of  uric  acid  was  supposed  to  be  proteid. 

Liebig  seems  to  have  been  fully  convinced  that  uric  acid  is  a 
partial  oxidation  product  of  proteid.  He  stated^  that  if  people 
dwelling  in  cities  who  suffer  from  uric  acid  concretions  go  to 
the  country,  where  they  breathe  more  oxj-gen,  they  often  get 
concretions  of  oxalic  acid,  an  oxidation  product  of  uric  acid. 
If  they  exercise,  and  thus  breathe  still  more  oxygen,  the  uric 
acid  is  oxidized  completely  to  urea  and  COj.  In  the  urine  of 
animals  which  drink  much  water  there  is,  according  to  Liebig, 
less  uric  acid  than  in  other  animals;  water  keeps  the  sparingly 
soluble  uric  acid  in  solution,  and  it  is  therefore  more  completely 
oxidized  to  urea. 

Bartels  ^  tried  to  show  that  an  increased  excretion  of  uric  acid 
is  due  to  a  disturbance  of  the  relation  between  the  need  and  the 
supply  of  oxygen,  that  there  is  always  in  such  a  case  a  relative 
insufficiency  in  the  amount  of  oxygen  supplied  to  the  tissues. 
Lehmann  ^  had  observed  an  increased  excretion  of  uric  acid  in 
fevers.  Bartels,  however,  maintained  that  this  only  occurred 
when  with  the  fever  there  was  also  a  relatively  insufficient  oxygen 
supply.  Bartels  found  the  excretion  of  uric  acid  increased  in 
chlorosis  and  leukemia,  and  attributed  it  to  diminished  internal 
respiration  due  to  lack  of  red  blood  corpuscles.  Meyer*  had 
found  that  in  carbon  monoxide  poisoning  the  CO  combines  with 
the  red  blood  corpuscles  to  form  a  compound  so  stable  that  the 
CO  is  not  replaced  by  oxygen,  and  therefore  the  red  blood  cor- 
puscles do  not  take  up  oxygen.  Bartels  found  increased  excre- 
tion of  uric  acid  in  cases  of  carbon  monoxide  poisoning,  in  which 
he  has  been  confirmed  by  Munzer  and  Palmer.^  This  again 
seemed  to  confirm  his  theory.  Jacubasch,''  who  likewise  found 
increased  uric  acid  excretion  in. leukemia,  attributed  it  to  insuffi- 

1  J.  Liebig.  Animal  Chemistry,  or  Organic  Chemistry  in  its  Application  to  Physiology 
and  Pathology.     Transl.  of  W.  Gregory.     Ed.  by  J.  Webster,  Cambridge  (1843). 

2  Bartels.  Untersuchungen  iiber  die  Ursache  einer  gesteigerten  Ausscheidung  der 
Harnsaure  in  Krankheiten.     Deutsche  Arch,  fur  klin.  Medizin,  1,  13  (1866). 

3  Lehmann.     Handbuch  der  physiol.  Chemie,  1,  218  (1853). 

*L.  Meyer.  Die  Gase  des  Blutes.  Zeitsohr.  f  iir  rationnelle  Med.  NeueFolge,  8, 256  (1857). 

5  E.  Munzer  und  P.  Palmer.  Ueber  den  Stoffwechsel  des  Menschen  bei  Kohlendunst- 
und  Nitrobenzolvergiftung.     Zeitschr.  fiir  Heilkunde,  15,  1  (1894). 

^  H.  Jacubasch.  Beitrage  zur  Harnanalyse  bei  lienaler  Leukamie.  Virchow's  Archiv, 
43,  196  (1868). 


Physiology  169 

cient  oxidation.  Mosler  did  not  find  the  uric  acid  excreted  always 
increased  in  leukemia/  and  came  to  the  conclusion  that  this  in- 
creased excretion  occurred  only  when  with  the  leukemia  there 
was  at  the  same  time  a  relatively  insufficient  supply  of  oxygen 
to  the  tissues.^ 

A  further  apparent  confirmation  of  Bartels'  theory  was  seen  in 
the  work  of  Kollmann,^  Eckhardt/  and  Sticker.^  These  authors 
found  that  the  high  uric  acid  in  leukemia  and  emphysema,  which 
was  explained  as  due  respectively  to  deficient  internal  and  ex- 
ternal respiration,  could  be  decreased  by  oxygen  inhalation.  The 
work  of  J.  Ranke^  and  others  who  found  the  uric  acid  in  the 
urine,  like  the  urea,  dependent  on  the  proteid  of  the  diet,  was 
considered  another  confirmation  of  the  theory  that  uric  acid  comes 
from  proteid. 

The  work  of  Nencki  and  Sieber  ^  was  also  an  apparent  confirma- 
tion of  the  view  that  in  leukemia  there  is  a  condition  of  dimin- 
ished oxidation.  These  authors  proposed  to  measure  the  power 
of  oxidation  of  the  organism  under  different  conditions  by  com- 
paring the  different  amounts  of  benzene  that  could  be  oxidized 
to  phenol.  They  found  that  in  leukemia  less  phenol  was  formed 
from  a  definite  amount  of  benzene  than  normally.  It  is  of  inter- 
est that  they  did  not  find  a  condition  of  decreased  oxidation  by 
their  method  in  chlorosis  and  anemia.  Kraus  and  Chwostek  ^ 
by  this  same  method  could  not  observe  a  condition  of  decreased 
oxidation  in  leukemia.  The  method  of  Nencki  and  Sieber  has 
been  shown  to  be  useless. 

We  have  spoken  before  of  the  theory  of  Mares  ,^  that  the  uric 

1  F.  Mosler  und  W.  Korner.  Zur  Blut-  und  Harnanalyse  bei  Leukamie.  Virchow's 
Archiv,  25,  142  (1862). 

2  F.  Mosler.  Zur  Diagnose  der  lienalen  Leukamie  und  der  chemischen  Beschaffenheit 
der  Transudate  und  Sekrete.     Virchow's  Archiv,  37,  43  (1866). 

SKollmann.     Miinchener  artzl.  Intelligenzblatt,  17,  No.  22  (1869). 

^  Eckhardt.  Die  acute  Gicht  und  ihre  Behandlung.  (Cited  by  Sticker.  Zeitschr.  fiir 
klin.  Medizin,  14,  80  [1888]). 

5  G.  Sticker.  Beitrage  zur  Pathologie  und  Therapie  der  Leukamie.  Zeitschr.  fiir  klin. 
Medizin,  14,  80  (1888). 

8  J.  Ranke.  Kohlenstoff-  und  Stickstoff-Ausscheidung  des  ruhenden  Menschen.  Arch. 
f.  Anat.  u.  Physiol.,  311  (1862). 

^  M.  Nencki  und  N.  Sieber.  Ueber  eine  neue  Methode,  die  physiologische  Oxydation 
zu  messen  und  iiber  den  Einfluss  der  Gifte  und  Krankheiten  auf  dieselbe.  Pfliiger's 
Archiv,  31,  319  (1883). 

8  F.  Kraus  und  F.  Chwostek.  Ueber  den  Einfluss  von  Krankheiten  auf  den  respira- 
torischen  Gaswechsel  und  iiber  die  Sauerstofftherapie.  Wiener  klin.  Wochenschrift,  4, 
605  (1891). 

s  Mares.  Sur  I'origine  de  I'acide  urique  chez  rhomme.  Archives  slaves  de  Biologie,  3, 
207  (1888),  and  Centralblatt  fiir  Med.  Wissensch.,  26,  2  (1888). 


170      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

acid  owes  its  formation  to  the  activity  of  the  body  cells,  especially 
the  cells  of  the  digestive .  glands.  Mares,  therefore,  considered 
proteid  as  the  source  of  uric  acid. 

Stadthagen  ^  attempted  to  increase  the  excretion  of  uric  acid 
by  feeding  purin  bases  and  nucleins.  He  obtained  negative 
results  and  therefore  returned  to  the  old  idea  that  uric  acid  is 
derived  from  proteid.  The  absolute  dependence  of  the  amount 
of  uric  acid  excreted  on  the  proteid  of  the  diet,  and  its  absolute 
independence  of  the  amount  of  purin  bodies  in  the  food  which 
seemed  apparent  to  him,  he  considered  proof  of  his  view.  He  also 
called  attention  to  the  fact  that  starving  persons  who  eat  no  purin 
bodies  still  excrete  uric  acid,  and  that  suckling  children,  who  receive 
no  purin  bodies  as  food,  excrete  relatively  large  amounts  of  uric 
acid.  The  true  explanation  of  the  facts  cited  by  Stadthagen  as 
proof  of  his  theory  is  now  apparent,  as  we  have  already  seen. 

The  theory  that  the  presence  of  uric  acid  in  the  urine  is  due  to 
incomplete  oxidation  had  opponents  even  before  the  true  source 
of  uric  acid  was  known.  Thus  Panum^  found  that  after  bleed- 
ing dogs,  although  they  had  thereby  suffered  a  considerable  loss 
of  red  blood  corpuscles,  the  internal  respiration  was  unchanged; 
there  was  no  change  in  the  amount  of  oxygen  taken  in  and  the 
amount  of  carbon  dioxide  formed.  It  was  not  possible,  appar- 
ently, to  affect  the  oxidizing  power  of  the  organism. 

Voit^  found  that  neither  by  section  of  the  vagus,  formation 
of  a  pneumothorax,  or  bleeding,  whereby  the  respiration  was 
disturbed,  could  he  decrease  the  amount  of  oxygen  taken  in  or 
the  carbon  dioxide  given  out.  Senator  ^  bound  tightly  the 
thorax  of  a  number  of  dogs,  cats,  and  rabbits  in  an  attempt  to 
decrease  the  external  respiration.  He  found,  how^ever,  that, 
except  in  the  cases  of  two  of  the  dogs,  there  was  no  increased 
excretion  of  uric  acid.     Even  in  leukemia,  Pettenkofer  and  Voit,^ 

1 1  M.  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaure  in  verscheidenen  tierisclien 
Organen,  ihr  Verhalten  bei  der  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  Stick- 
stoffbasen.     Virchow's  Archiv,  109,  390  (1887). 

^  P.  Panum.  Experimentelle  Untersuchungen  tiber  die  Transfusion,  Transplantation, 
Oder  Substitution  des  Blutes  in  theoretischer  und  practischer  Beziehung.  Virchow's 
Archiv,  27,   433    (1863). 

3  C.  Voit.  Ueber  das  Gaswechsel  nach  Durchschneidung  der  nervi  vagi.  Sitzungsber. 
d.  konigl.  bayerischen  Akad.  de  Wissenschaft,  2,  104  (1868). 

^  H.  Senator.  Experimentelle  Untersuchungen  iiber  den  Einfluss  von  Respirations- 
storungen  auf  den  Stoffwechsel.     Virchow's  Archiv,  42,  1  (1868). 

^  M.  V.  Pettenkofer  und  C.  Voit.  Ueber  den  Stoffverbrauch  bei  einem  leukamischen 
Manne.     Zeitschr.  fur  Biol.,  5,  319  (1869). 


Physiology  171 

Kraiis  and  Chwostek/  and  Bohland  ^  found  that  the  respiration  is 
not  affected.  The  amount  of  oxygen  taken  in  and  the  amount 
of  carbon  dioxide  expelled  were  the  same  as  in  health  on  the 
same  food.  Naunyn  and  Reiss  ^  found  that  loss  of  blood  does 
not  influence  the  amount  of  uric  acid  excreted. 

The  theory  that  urea  has  passed  through  the  stage  of  uric  acid 
in  its  formation  out  of  proteid  never  had  any  proof.  It  was  a 
mere  hypothesis.  On  the  other  hand,  we  have  already  seen  that 
the  quahty  and  quantity  of  the  proteid  of  the  food  has  no  influ- 
ence on  the  amount  of  uric  acid  excreted.  The  influence  of  the 
food  is  due  solely  to  the  purin  bases  in  it.  These  bodies  oxidize 
to  uric  acid.  Furthermore,  neither  uric  acid  nor  the  purin  bases 
have  ever  been  obtained  as  decomposition  or  oxidation  products 
of  proteid.  Since,  too,  as  we  have  seen,  uric  acid  injected  into 
the  circulation  is  excreted  in  large  part  unchanged,  it  is  probable 
that  if  it  were  formed  as  an  intermediate  product  in  the  destruc- 
tive metabolism  of  proteid,  it  would  be  excreted  in  larger  quan- 
tities. 

THE  QUESTION  OF  THE  SYNTHESIS  OF  URIC  ACID  IN  THE 

BODY 

From  Glycocoll  and  Urea 
The  "  fruit  cures  "  have  often  been  recommended  in  gout. 
Thiis,  cherries  had  been  thought  by  Wohler  and  strawberries 
and  grapes  by  Linne^  to  give  clinically  good  results  in  gout. 
Citron  has  also  been  highly  recommended.  Weiss  ^  confirmed  the 
clinical  results  of  the  older  writers  and  found  that  the  uric  acid 
in  the  urine  is  decreased  and  the  hippuric  acid  increased  by  a  diet 
containing  a  large  amount  of  fruit.  He  found  on  investigation 
that  quinic  acid  (hexahydrotetroxybenzoic  acid)  is  the  active 
agent  which  brings  about  these  results.  In  a  later  article  he 
explained  how  the  quinic  acid  acts.^     Wohler  had  shown  that 

1  F.  Kraus  und  F.  Chwostek.  Ueber  den  Einfluss  von  Krankheiten  auf  deH  respirato- 
rischen  Gaswechsel  und  iiber  die  Sauerstofftherapie.  Wiener  klin.  Wochenschrift,  4,  605 
(1891). 

2  K.  Bohland.  Ueber  den  respiratorischen  Gaswechsel  bei  verscheidenen  Formen  der 
Anamie.     Berl.  klin.  Wochensohrift,    30   417  (1893). 

3  B.  Naunyn  und  L.  Reiss.  Ueber  Harnsaureausscheidung.  Du  Bois  Archiv,  fur  Anat. 
und  Physiol.,  381  (1869). 

^  Ebstein.     Das  Reginnen  bei  der  Gicht.     Wiesbaden  (1885),  p.  49. 

6  J.  Weiss.  Beitrage  zur  Erforschung  der  Bedingungen  der  HarnsaurebUdung.  Zeit- 
schr.  fiir  physiol.  Chem.,  25,  393  (1898). 

3  Ibid.  Eine  neue  Methode  der  Behandlung  der  Harnsaiu-e  Diathese.  Berl.  klin. 
Wochenschrift,  36,  297  (1899). 


172      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

hippuric  acid  is  synthesized  in  the  body  from  glycocoll  and  ben- 
zoic acid.  It  had  been  shown  also  that  quinic  acid  reduces  to 
benzoic  acid  and  then  forms  hippuric  acid  with  glycocoll.  Ac- 
cording to  Weiss,  uric  acid  is  formed  by  synthesis  from  glycocoll 
and  urea,  and  quinic  acid,  after  oxidation  to  benzoic  acid,  de- 
creases the  amount  of  uric  acid  formed  by  using  up  the  glycocoll 
formed  as  intermediate  product  to  form  hippuric  acid. 

Wohler  *  had  previously  noted  an  opposition,  so  to  speak, 
between  uric  acid  and  hippuric  acid.  In  the  urine  of  suckling 
calves  he  found  uric  acid  but  no  hippuric  acid.  When  the  milk 
diet  was  replaced  by  a  purely  vegetable  diet,  uric  acid  disappeared, 
and  hippuric  acid  appeared.  These  observations  of  Wohler 
were  contradicted  by  Horbaczewski  ^  and  Weiss.^  Maly*  had 
previously  expressed  the  view  that  uric  acid  may  be  formed  in 
the  body  by  synthesis  from  glycocoll,  and  that  administration 
of  benzoic  acid  ought  to  use  up  the  glycocoll  necessary  for  the 
synthesis.  He  found  experimentally,  however,  that  benzoic  acid 
does  not  decrease  the  excretion  of  uric  acid. 

The  views  of  Weiss  seemed  very  plausible.  Strecker  ^  had 
shown  that  "  extra  corpus  "  uric  acid  can  be  decomposed  into 
glycocoll  carbon  dioxide  and  ammonia,  and  Horbaczewski  ^  had 
shown  that  uric  acid  can  be  synthesized  in  the  laboratory  from 
glycocoll  and  urea.  Direct  attempts  to  synthesize  uric  acid  in 
the  body  by  administration  of  glycocoll  and  urea  gave  negative 
results.^  On  the  other  hand,  we  have  known  since  Wohler's  ^ 
experiment  in  1824  that  benzoic  acid  unites  with  glycocoll  in 
the  organism  to  form  hippuric  acid.  Lautemann^  showed  that 
quinic  acid  reduces  to  benzoic  acid  outside  the  body,  and  also, 
as  we  might  expect,  that  quinic  acid  changes  to  hippuric  acid 

1  Wohler.     Nachr.  d.  k.  Ges.  d.  Wissensch.,  zu  Gottingen  (1849),  5,  p.  61. 

2.T.  Horbaczewski.     Beitrage  ziir  Kenntniss  der  Bildung  der  Harnsaure.     Wien  (1891). 

3  J.  Weiss.  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung.  Zeitschr. 
fiir  physiol.  Ghem.,  25,  393  (1898). 

*  R.  Maly.  Ueber  das  Verhalten  der  Oxybenzoesaure  und  Paraoxybenzoesaure  in  der 
Blutbahn.     Sitzungsber.  der  Wiener  Akad.  d.  Wissensch.,  65,  2.  Abt.,  39  (1872). 

'  A.  Strecker.  Bildung  von  Glycocoll  aus  Harnsaure.  Ann.  der  Chem.  u.  Pharm., 
146,  142  (1868). 

6  J.  Horbaczewski.     Synthase  der  Harnsaiire.     Monatshefte  fiir  Chemie,  3,  796  (1882). 

'  Ihid.  Weitere  synthetische  Versuche  iiber  die  Konstitution  der  Harnsaure 
und  Bemerkungen  iiber  die  Entstehung  derselben  im  Tierkorper.  Monatshefte  fiir 
Chemie,  8,  584  (1887). 

8  Berzelius  Lehrb.  d.  Chem.     German  translation  of  Wohler,  Vol.  4,  Dresden  (1831). 

'  E.  Lautemann.  Ueber  die  Reduktion  der  Chinasaure  zu  Benzoesaure  und  die  Ver- 
wandlung  derselben  in  Hippursaure  im  thierischen  Organismus.  Ann.  der  Chem.  u. 
Pharm.,  CXXV,  9  (1863). 


Physiology  173 

when  introduced  into  the  organism.  Mattschersky/  Meissner 
and  Shepard,"  and  Lewin  ^  also  found  that  quinic  acid  changes  to 
hippuric  acid  in  the  organism.  Liicke  ^  found  that  berries  and 
vegetables  give  an  increased  excretion  of  hippuric  acid,  and  Loewi  ^ 
found  that  it  is  the  quinic  acid  in  hay  from  which  the  large  amount 
of  hippuric  acid  in  the  urine  of  horses  and  cows  is  derived.  It 
is  very  certain,  then,  that  quinic  acid  changes  to  benzoic  acid  in 
the  animal  organism  and  unites  with  glycocoll  to  form  hippuric 
acid,  and  it  seemed  very  possible  that  glycocoll  unites  with  urea 
to  form  uric  acid. 

Lewin  ^  confirmed  Weiss 's  view  that  quinic  acid  decreases  the 
excretion  of  uric  acid.  Weiss  "^  performed  one  experiment  of  three 
days'  duration  in  which  he  thought  he  found  that  the  increased 
excretion  of  uric  acid  after  thymus  feeding  was  prevented  by 
quinic  acid.  The  results  of  that  experiment,  however,  do  not 
warrant  his  conclusion.    The  quinic  acid  had  practically  no  effect. 

Richter''  found  that  the  uric  acid  concretions  produced  in 
birds  by  potassium  chromate  injections  are  not  so  bad  when 
quinic  acid  in  the  form  of  its  piperazin  salt  is  given.  But  Rich- 
ter's  experiments  were  performed  on  birds,  and  in  birds  the 
nitrogenous  metabolism  differs  from  that  of  mammals.  Further, 
according  to  the  experiments  of  Ortowski,^  Meisls,^  and  Biesen- 
thal,^"  piperazin  itself  prevents  the  formation  of  these  concretions. 

As  a  result  of  the  work  of  Weiss,  several  preparations  contain- 
ing quinic  acid,  for  example,  the  lithium,  piperazin,  urea,  and 
urotropin  salts,    called   respectively   urosin,   sidonal,   urol,    and 

1  p.  Mattschersky.     Zur  Entstehung  der  Hippursaure.  Virchow's  Archiv,  28,  538  (1863). 

2  Meissner  und  Shepard.  Untersuchungen  liber  die  Bildung  der  Hippursaure.  Han- 
over (1866). 

3  C.  Lewin.  Beitrage  zum  HippursaurestoflEwechsel  des  Menschen.  Zeitschr.  fiir  kUn. 
Medizin,  42,  371  (1901). 

^  A.  Liicke.  Ueber  die  Anwesenheit  der  Hippursaure  im  menscUichen  Ham  und  ihre 
Auffindung.     Virchow's  Archiv,  19,  196  (1860). 

5  O.  Loewi.  Ueber  die  Quelle  der  Hippursaure  im  Ham  der  Pflanzenfresser.  Journ.  fiir 
prakt.  Chem.,  19,  309  (1879). 

*  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Hamsaurebildung. 
Zeitschr.  fiir  physiol.  Chem.,  27,  216  (1899). 

'  P.  Richter.  Ueber  die  experimenteUe  Priifung  sogen.  "  Gichtsmittel  "  in  Allge- 
meinen  und  iiber  die  Chinasaure  und  Chinasaure  Piperazin  im  Besonderen.  Charit^e 
Annalen,  25,  196  (1900). 

8  W.  Ortowski.  Vergleichende  Untersuchungen  iiber  Urotropin,  Piperazin,  Lysidin, 
Uricedin,  und  Natronbicarbonicum  bei  der  harnsauren  Diathese.  Zeitschr.  fur  klin.  Med- 
izin, 40,  331   (1900). 

9  Meisls.     Ungarisches  Archiv.  fiir  Med.,  Vol.  I.,  Heft  (5-6),  (1893). 

1"  P.  Biesenthal.  Wirkung  des  Piperazins  bei  kunstlich  erzeugten  Harnsaureablager- 
ungen  im  thierischen  Organismus.     Berl.  klin.  Wochenschrift,  30,  805  (1893"). 


174      The  Chemistry ,  Physiology,  and  Pathology  of  Uric  Acid 

chinatropin,  also  others  called  ursal,  uropherin,  uropherinben- 
zoate,  urotropinsalicylate,  etc.,  were  recommended  and  found 
of  clinical  value  in  gout  by  Weiss/  Mylius,^  Blumenthal,^  Stern- 
feld/  Salfeld,^  v.  Leyden,^  Meyer ,^  Ewald,^  Golds cheider,^  von 
Lang,^  and  others.  These  clinical  observations  are,  of  course, 
not  a  confirmation  of  the  theory  that  uric  acid  can  be  synthesized 
from  glycocoll  and  urea,  although  Weiss  ^  has  recently  tried  to 
defend  his  theory  by  using  these  clinical  results  as  evidence.  It 
is  a  peculiar  fact  that  all  those  chemical  compounds  whose  use  in 
gout  has  been  based  on  scientific  observations  or  pure  theory 
have  been  found  clinically  of  value  by  some  observers,  and  even 
after  the  scientific  observations  and  theories  upon  which  their 
use  has  been  based  have  been  proved  faulty  and  erroneous,  many 
good  clinicians  have  still  clung  to  them  as  possessing  some  good, 
though  perhaps  unexplained,  action.  This  has  been  true  of  the 
inorganic  alkaline  compounds  of  sodium,  potassium,  and  lithium, 
of  the  organic  alkaline  bodies  of  which  piperazin  and  kreatin  are 
examples,  of  urea,  and  other  bodies,  as  well  as  the  compounds 
of  quinic  acid,  and  indicates  what  caution  must  be  used  in 
accepting  clinical  observations. 

Mattschersky,^  Meissner  and  Shepard,^  and  Schultzer  and 
Grabe  ^^  confirmed  Wohler's  work  showing  that  benzoic  acid 
becomes  excreted  as  hippuric  acid,  and  also  Lautemann's  work 
showing  that  quinic  acid  is  excreted  as  hippuric  acid.  They 
also  showed  that  a  number  of  other  acids  which  are  derivatives 

1  J.  Weiss.  Die  Chinasaure  als  Antiarthriticum.  Klin.-therap.  Wochenschrift,  6, 
1544  (1899),  also 

Die  Erfolge  der  Urosinbehandlung  bei  harnsaurer  Diathese.  Verhandl.  des  18  Kongr. 
fiir  innere  Med.   (1900),  477. 

2  Mylius.     Ueber  die  Einwirkung  des  Sidonal  bei  Gicht,  14,  658  (1900). 

3  Blumenthal.  Ueber  Sidonal,  ein  neues  Gichtmittel.  Miinchen.  med.  Wochenschrift, 
47,  372  (1900),  and  discussion  by  v.  Leyden,  J.  Meyer,   Ewald,  Goldscheider,  and  Meyer. 

Blumenthal  und  Lewin.     Therapie  der  Gegenwart  (1900),  Heft  4. 

*  H.  Sternfeld.  Die  Chinasaure  ein  neues  Heilmittel  gegen  Gicht.  Miinchen.  med. 
Wochenschrift,  48,  260  (1901). 

■''  Salfeld.  Zur  Behandlung  der  Gicht  mit  Chinasaure.  Miinchen.  med.  Wochenschrift, 
April   (1901). 

6  K.  von  Lang.  Ueber  ein  neues  harnsaurelosendes  Mittel,  das  Urosin.  Klin.-therap. 
Wochenschrift,  Wien,  10,  247  (1903). 

'  J.  Weiss.  Erwiderung  auf  die  Arbeit  des  Herrn  Dr.  Hupfer.  Zeitschr.  fiir  physiol. 
Chem.,  38,  198  (1903). 

8  P.  Mattschersky.  Zur  Entstehung  der  Hippursaure.  Virchow's  Archiv,  28,  538 
(1863). 

9  Meissner  und  Shepard.     Untersuchungen  iiber  die  BUdung  der  Hippursaure.     Han- 
over (1866). 

If"  O.  Schultzer  und  C.  Grabe.  Ueber  das  Verhalten  der  aromatischen  Sauren  im  Organ- 
ismus.     Arch,  fiir  Anat.  und  Physiol.  166  (1867). 


Physiology  175 

of  benzoic  acid,  among  them  salicylic  acid,  act  like  benzoic  acid 
and  quinic  acid  in  this  respect. 

We  should  expect,  then,  that  benzoic  acid  and  salicylic  acid 
would  likewise  decrease  the  excretion  of  uric  acid.  Yet  neither 
Maly,^  Lewandosky,^  or  Schreiber  and  Waldvogel  ^  could  ob- 
serve that  benzoic  acid,  nor  Bain  *  that  lithium  benzoate,  has  any 
effect  on  the  excretion  of  uric  acid.  Only  Ulrici  ^  observed  a 
slightly  decreased  excretion  of  uric  acid  after  administration  of 
benzoic  acid.  Salicylic  acid,  in  fact,  increases  the  excretion  of 
uric  acid  according  to  Schreiber  and  Waldvogel,^  Ulrici,  ^  Lewan- 
dosky,^  Kumagawa,^  Bohland,^  Haig,^  Bouchard,''  Lecorche,^" 
Magnus-Levy,"  Byasson,^^  and  Salome. ^^ 

As  direct  proof  against  the  views  of  Weiss,  we  have  the  re- 
searches of  Ulrici,^  Nicolaier,"  Nicolaier  and  Hagenburg,^^  Foer- 
ster,"  Lewandosky,^  and  Hupfer,^^  which  show  that  quinic  acid 
has  no  influence  on  the  excretion  of  uric  acid.  Hupfer  found 
that  administration  of  even  25  grams  of  quinic  acid  per  day  had 

1  R.  Maly.  Ueber  das  Verhalten  der  Oxybenzoesaure  und  Paraoxybenzoesaure  in  der 
Blutbahn.     Sitzungsber.  der  Wiener  Akad.  d.  Wissensch.,  65,  2.  Abt.  39  (1872). 

2  M.  Lewandosky.  Versuche  iiber  den  Einfluss  der  Benzoesaure  auf  die  Harnsaure- 
bildung.     Zeitschr.  fiir  klin.  MedizLn,  40,  202  (1900). 

3  Schreiber  und  Waldvogel.  Beitrage  zur  Kenntniss  der  Harnsaureausscheidung  unter 
physiologischen  und  pathologischen  Verhaltnissen.  Arch,  fiir  exp.  Path.  u.  Pharmak.,  42, 
69  (1899). 

^  W.  Bain.  The  Influence  of  Some  Modern  Drugs  on  MetaboUsm  in  Gout.  Brit.  Med. 
Journ.  (1903),  1,  243. 

5  H.  Ulrici.  Ueber  pharmakologische  Beeinflussung  der  Harnsaureausscheidung. 
Arch,  fiir  exp.  Path.  u.  Pharmak,  46,  321  (1901). 

8  Kunaagawa.  Ueber  die  Einwirkung  einiger  antipyretischen  Mittel  auf  den  Eiweiss- 
umsatz  im  Organismus.     Virchow's  Archiv,  113,  134  (1888). 

'  Bohland.  Ueber  den  Einfluss  des  saUcylsauren  Natrons  auf  die  Bildung  und  Aus- 
scheidung  der  Harnsaure.     Centralblatt  fiir  inn  ere  Medizin,  17,  70  (1896). 

s  Haig.     Uric  Acid  in  Diseases.     37,  London  (1896). 

8  Bouchard.     Les  maladies  par  ralentissement  de  la  nutrition.     3  ed.,  306,  Paris  (1890). 

lOLecorche.     La  goutte,  584,  Paris  (1884). 

"  A.  Magnus-Levy.     Ueber  Gicht.     Zeitschr.  fiir  klin.  Medizin,  36,  412  (1899). 

12  Byasson.     Journ.  de  Th^r.,  Oct.  10,  1877. 

13  Salome.  Ueber  den  Einfluss  des  saUcylsauren  Natrons  auf  die  StickstofI  und  Harn- 
saureausscheidung beim  Menschen.     Wiener  med.  Jahrbiicher,  4,  463  (1885). 

1^  Nicolaier.     Centralbl.  fiir  Stoffwechselkrankheiten  (1900). 

A.  Nicolaier.  Experimentelles  und  Klinisches  iiber  Urotropin.  Zeitschr.  fiir  klin. 
Medizin,  38,  356  (1899). 

15  Nicolaier  und  Hagenburg.  Ueber  Chinotropin.  Centralbl.  f.  Stoffwechsel  und 
Verdauungskrankheiten  1,  131  (1900),  also  Maly's  Jahresber.  iiber  die  Fortschritte  der 
Thierchemie,  30,  616  (1900). 

16  Foerster.  Versuche  iiber  die  Beeinflussung  der  Harnsaiu-eausscheidung  mit  specieUer 
Beriicktsichtigvmg  der  Chinasaure  imd  der  chinasauren  Salze.  Inaug.  Dissert,  Breslau 
(1900). 

"  F.  Hupfer.  Einwirkung  von  Chinasaure  auf  Harnsaiire  und  Hippursaureausscheidung. 
Zeitschr.  fiir  physiol.  Chem.,  37,  302  (1903). 

F.  Hupfer.     Entgegnung  an  Dr.  J.  Weiss.     Zeitsch.  fiir  physiol.  Chem.,  40,  315  (1903). 


176      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

no  influence  on  the  excretion  of  uric  acid.  He  found  likemse 
that  the  addition  of  large  amounts  of  cherries  and  grapes  had  no 
effect  on  the  excretion  of  uric  acid.  His^  found  that  citron  does 
not  influence  the  excretion  of  uric  acid.  Bain  ^  could  not  find 
that  sidonal  has  any  effect  on  the  excretion  of  uric  acid.  Quinic 
acid  does  not  affect  the  excretion  of  uric  acid  in  dogs,  according 
to  Taltavall  and  Gies.^ 

Blumenthal^  and  De  la  Camp^  found  that  quinic  acid  some- 
times decreases  the  excretion  of  uric  acid  and  sometimes  has  no 
effect.  The  explanation  they  gave  was  that  quinic  acid  decreases 
the  amount  of  uric  acid  coming  from  the  purin  bodies  of  the  food, 
but  does  not  influence  the  amount  derived  from  the  body  cells. 
This  explains,  a^ccording  to  them,  the  contradictory  results  of 
different  experimenters.  This,  however,  can  scarcely  be  true, 
since  Hupfer's  results  show  no  influence  of  quinic  acid  on  the  uric 
acid  excretion,  yet  judging  from  the  size  of  the  uric  acid  excre- 
tion, 0.8  to  0.9  gram  per  day,  there  must  have  been  purin  bodies  in 
the  diet.  xVnd  besides,  we  know  now  that  the  exogenous  uric  acid 
comes  only  from  oxidation  of  purin  bodies  of  the  food,  and  there- 
fore if  cpinic  acid  has  anj^  influence  on  this  uric  acid,  Weiss 's 
explanation  could  not  apply. 

In  a  series  of  experiments  carried  out  over  two  decades  ago,^ 
E.  and  H.  Salkowski  showed  that  phenylpropionic  acid  is  formed 
in  intestinal  putrefaction  of  proteid,  and  that  this  compound 
changes  to  benzoic  acid,  unites  with  glycocoll,  and  is  excreted  as 
hippuric  acid.      Baumann^  showed  that  if  the  intestines  be  kept 

1  W.  His.  Die  Ausscheidung  von  Hamsaure  im  Urin  der  Gichtkranken  mit  besonderer 
Beriicksichtigung  der  Anfallszeiten  und  bestunmter  Behandlungsmethoden.  Deutsche 
Arch,  fur  klin.  Medizin,  65,  156  (1900). 

2  W.  Bain.  The  Influence  of  Some  Modern  Drugs  on  the  Metabolism  in  Gout.  Brit. 
Med.  Journ.,  1,  243  (1903). 

3  W.  TaltavaU  and  W.  Gies.  The  Influence  of  Chinic  Acid  on  the  EUmination  of  Uric 
Acid.     Proc.  Am.  Physiol.  Soc,  Boston  (1903),  p.  xvi;  Am.  Journ.  of  Physiel.,  9,  16  (1903). 

*  F.  Blumenthal.  Ueber  die  Ausscheidung  der  Hamsaure  nach  Darreichung  von  China- 
saure.     Charit^e  Annalen,  25,  34  (1900). 

5  De  la  Gamp.     Chinasaure  und  Gicht.     Miinchen.  med.  Wochenschrift,  48,  1203  (1901) 

6  E.  Salkowski  und  H.  Salkowski.  Ueber  die  Verdauung  von  Hydrozimmtsaure  bei 
der  Pankreasverdauung.     Ber.  der  Dtsch.  chem.  GeselL,  12,  107  (1879). 

Weitere  Beitrage  zur  Kenntniss  der  Faulnissprodukte  des  Eiweiss.  Ber.  der.  Dtsch. 
chem.  GeseU.,  12,  652  (1879). 

Ueber  das  Verhalten  der  Phenylessigsam-e  und  Phenylpropionsaure  im  Organismus. 
Ber.  der  Dtsch.  chem.  GeselL,  12,  653  (1899). 

Ueber  das  Verhalten  der  aus  dem  Eiweiss  durch  Faulniss  entstehenden  aromatischen 
Sainen  im  Thierkorper.     Zeitschr.  fur  physiol.  Chem.,  7,  161  (1882). 

^  E.  Baumann.  Die  aromatischen  Verbindungen  im  Harn  und  die  Darmfaulniss. 
Zeitschr.  fiir  physiol.  Chem.,  10,  129  (1886). 


Physiology  177 

sterile,  no  phenylpropionic  acid  is  formed,  and  no  hippuric  acid 
is  found  in  the  urine.  Weintraud  ^  completed  this  work  by  show- 
ing that  the  excretion  of  hippuric  acid  is  parallel  with  the  intes- 
tinal putrefaction  as  expressed  by  the  amount  of  sulphonic  acid 
in  the  urine.  These  experiments  indicate  that  the  formation  of 
uric  acid  and  of  hippuric  acid  are  entirely  independent  processes. 
Since  Weintraud  ^  found  that  as  much  as  24  grams  of  benzoic  acid 
could  be  eaten  without  any  appearance  of  it  in  the  urine,  it  seems 
probable  that  the  organism  is  capable  of  forming  considerable 
quantities  of  glycocoll  as  an  intermediate  product  of  metabolism, 
a  quantity  many  times  more  than  ever  appears  as  uric  acid,  even 
if  we  assume  that  all  the  uric  acid  excreted  comes  from  glycocoll 
by  synthesis. 

Weintraud  found  that  the  hippuric  acid  excretion  is  often, 
but  not  always,  increased  after  thymus  feeding.  He  showed, 
however,  that  the  hippuric  acid  excretion  is  parallel  with  the 
excretion  of  sulphonic  acid  in  these  cases,  and  as  the  latter  is  an 
indication  of  intestinal  putrefaction,  the  increased  excretion  of 
hippuric  acid  is  due  probably  to  an  increase  in  the  phenylpro- 
pionic acid,  which  also  comes  from  intestinal  putrefaction  and 
not  from  glycocoll. 

The  theory  that  quinic  acid  should  decrease  the  excretion  of 
uric  acid  is  based  on  the  hypothesis  that  at  least  a  part  of  the 
uric  acid  excreted  is  formed  by  synthesis  from  glycocoll  and  urea. 
This  hypothesis  has  no  proof.  Neither  Horbaczewski  ^  nor 
Weiss  ^  could  observe  any  increased  excretion  of  uric  acid  after 
the  administration  of  glycocoll  in  the  food. 

From  Lactic  Acid  and  Urea 

After  Minkowski's  ^  experiments  on  geese  with  extirpated  livers 
in  which  he  showed  that  such  birds  excrete  large  amounts  of 
ammonium  lactate,  it  seemed  that  possibly  in  the  mammal 
organism  uric  acid  might  be  formed  by  synthesis  from  lactic 

1 W.  Weintraud.  Ueber  den  Abbau  des  Nukleins  im  Stoffwechsel.  Verhandl.  des 
18  Kongr.  fiir  innere  Med.,  232  (1900). 

-  J.  Horbaczewski.  Weitere  synthetische  Versuche  iiber  die  Konstitution  der  Harn- 
saure  imd  Bermerkungen  iiber  die  Entstehung  derselben  im  Tierkorper.  Monatshefte  fiir 
Chemie,  8,  584  (1887). 

3  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fiir  physiol.  Chem.,  27,  216  (18  99). 

^  O.  Minkowski.  Ueber  den  Einfiuss  der  Leberextirpation  auf  den  Stoffwechsel.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  21,  89  (1886). 


178      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

acid  and  urea.  This  idea  was  strengthened  by  the  fact  that  in 
the  following  year  Horbacszewski^  succeeded  in  synthesizing  uric 
acid  "  extra  corpus  "  from  urea  and  trichlorlactic  acid.  Direct 
experiments  by  Herrmann,^  Weiss ,^  and  Minkowski  *  show,  how- 
ever, that  lactic  acid  taken  into  the  stomach  does  not  increase 
the  excretion  of  uric  acid. 


From  Glycerin  and  Urea 

Horbaczewski  and  Kanera  ^  found  that  glycerin  caused  increased 
excretion  of  uric  acid  in  man,  but  although  the  constitutional 
structure  of  glycerin  is  somewhat  similar  to  that  of  lactic  acid, 
we  cannot  assume  that  the  increased  excretion  of  uric  acid  is 
necessarily  due  to  a  synthesis  from  glycerin  and  urea,  for  Munk,® 
Tscherwinsky,^  and  Lewin  ^  have  shown  that  the  general  nitro- 
genous metabolism  also  is  increased  by  glycerin.  In  dogs, 
Wiener^  found  that  glycerin  does  not  give  increased  excretion  of 
uric  acid,  and  in  man  Weiss  ^  obtained  the  same  result. 

From  the  Monoureides  and  Urea 

Steudel  ^^  thought  that  some  of  the  monoureides,  such  as 
thymin,  which  is  a  decomposition  product  of  the  nucleoproteids, 
might,  with  urea,  be  synthesized  to  uric  acid.     He  administered 

1  J.  Horbaczewski.  Weitere  synthetische  Versuche  uber  die  Konstitution  der  Harn- 
saure  und  Bemerkungen  iiber  die  Entstehung  derselben  im  Tierkorper.  Monatshefte  fiir 
Chemie,  8,  584  (1887). 

2  A.  Herrmann.  Ueber  die  Abhangigheit  der  Harnsaureausscheidung  von  Nahrungs- 
und  Genussmitteln  mit  Rucksicht  auf  die  Gicht.  Deutsche  Arch,  fiir  klin.  Medizin,  43, 
273  (1888). 

3  J.  Weiss.  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung.  Zeitschr. 
fiir  physiol.  Chem.,  25,  393  (1898). 

*  D.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

5  Horbaczewski  und  Kanera.  Ueber  den  Einfluss  von  Glycerin,  Zucker,  und  Fett  auf 
die  Ausscheidung  des  Harnsaure  beun  Menschen.     Monatshefte  fiir  Chemie,  7,  105  (1886). 

Sitzungsber.  d.  kaiserl.  Akad.  d.  Wissensch.  zu  Wien,  93,  2  abth.,  583  (1886). 

6  I.  Munk.  Ob  Glycerin  ein  Nahrungstoff  ist.  Verhandl.  d.  physiol.  Gesell.  zu  Berlin 
(1878).     Arch.  f.  anat.  u.  physiol.,  565  (1878). 

'  N.  Tscherwinsky.  Ueber  den  Einfluss  des  Glycerins  auf  die  Zersetzung  des  Eiweisses 
im  Thierkorper.     Zeitschr.  fiir  Biol.,  15,  252  (1879). 

8  L.  Lewin.  Ueber  den  Einfluss  des  Glycerins  auf  den  Eiweissumsatz.  Zeitschr.  fiir 
Biol.,  15,  243  (1879). 

^  H.  Wiener.  Ueber  synthetische  Bildung  der  Harnsaure  im  Thierkorper.  Beitrage 
zur  chemisch.  Physiol,  und  Pathol.,  2,  42  (1902). 

1"  H.  Steudel.  Das  Verhalten  einiger  Pyrimidinderivate  im  Organismus.  Zeitschr.  fiir 
physiol.  Chem.,  32,  285  (1901). 


Physiology  179 

NH  — C— CH, 
I  II 

methyluracil  CO      CH 

NH  — CO 

NH  — C  — COOH  NH  — CH 

I  II  I  II 

nitrouracilic  acid,     CO       C  —  NOo      nitrouracil,       CO       C  —  NOj 

NH— CO  NH  — CO 

NH  —  CH  NH  —  CHOH 

I  II  II 

isobarbituric  acid,    CO      COH      isodialuric  acid,      CO      CO 

NH— CO  NH  — CO 

NH  —  CO  NH  —  CO 

11  II 

thymin,     CO       C  —  CHg  2-6-dioxypyrimidin,      CO       CH 
^              I           II  I  II 

NH  —  CH  NH  —  CH 


N  =  COH  N  =  CO 

i-amino-        xttt 
oxypyrimidin, 


and  di- and  tri-amino-        ^^        1       ^^      and    ^^^_   IJ,       I 


N  — CNHj  N  — CNH2 

to  dogs,  but  observed  no  increase  in  the  excretion  of  uric  acid. 
It  is  interesting  to  note  that  di-  and  tri-amino-oxy-pyrimidin, 
the  amino  derivatives  of  a  monoureide,  like  adenin, 

N  =  CNH, 

I  I 

CH    C—  NH\ 

II  II  )CH 
N  — C   —   N^ 

the  amino-  oxy-  di-ureide,  proved  toxic  to  dogs  and  rats  and  gave 
crystalUne  concretions  in  the  kidneys. 

In  a  later  series  of  experiments/  Steudel  found  that  feeding  of 
pseudouric  acid,  NH  —  CO 

CO        CH  —  NH.CONHo, 

NH  =  CO 

^  H.  Steudel.     Futterungsversuche  in    der    Pyrimidingruppe.     Zeitschr.  fiir    physiol. 
Chem.,  39,  136  (1903). 


180      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

NH  — CO 

isouric  acid,  CO       CH  -  NH.CN, 

I  I 

NH  —  CO 

NH  —  CH2 

or  hydrouracil,         '      CO       CH^,  did  not  lead  to  an  in- 

NH  —  CO 

creased  excretion  of  uric  acid  in  dogs.  Pseudouric  acid  easily 
changes  to  uric  acid  on  fusion  with  oxalic  acid.^  Isouric  acid 
changes  to  uric  acid  on  boiling  with  HCl.^  The  fact  that  Steu- 
del's  experiments  were  performed  upon  dogs  indicates  that  they 
are  of  doubtful  value  *as  conclusive  results. 

Minkowski  ^  attempted  to  obtain  an  increased  excretion  of 
uric  acid  in  dogs  by  administration  of  urea  and  allantoin,  but 
failed. 

From  Other  Compounds 

Hopkins  and  Hope  *  noticed  that  the  increased  excretion 
of  uric  acid  after  eating  meat  comes  more  quickly  than  the 
increase  in  the  excretion  of  urea.  Since  nuclein  is  absorbed 
only  in  the  intestines,  he  thought  the  increased  excretion  could 
not  be  due  to  nucleins.  These  authors  found  likewise  that  the 
extract  of  thymus  gland  freed  from  nuclein  by  digestion  with 
pepsin  hydrochloric  acid  gave  increased  excretion  of  uric  acid. 
They  thought,  therefore,  that  a  formation  of  uric  acid  in 
some  other  way  than  by  oxidation  of  purin  bodies,  prob- 
ably by  synthesis,  was  indicated.  Smith-Jerome  ^  found  that 
the  thymus  extract  of  Hopkins  and  Hope  contained  free  purin 
bases,  partly  present  originally  and  partly  formed  by  the  diges- 
tion of  the  thymus.  This  would  account  for  the  increased  excre- 
tion of  uric  acid. 

1  A.  Schlieper  und  A.  Baeyer.  Untersuchungen  iiber  die  Harnsauregruppe.  Liebig's 
Ann.  der  Chem.  u.  Pharm.,  127,  3  (1863). 

2  Mulder.  Ueber  die  Synthese  von  Harnsaure  und  iiber  Isoharnsaure.  Ber.  der  Dtsch. 
chem.  Gesell.,  6.  1235  (1873). 

3  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

^  F.  Hopkins  and  W.  Hope.  On  the  Relation  of  Uric  Acid  Excretion  to  Diet.  Journ.  of 
Physiol.,  23,  271  (1898). 

•'•  W.  Smith- Jerome.  Further  Proofs  of  the  Origin  of  Uric  Acid  from  Nuclein  Com- 
pounds and  Drivatives.     Journ.  of  Physiol.,  25,  98  (1899). 


Physiology  181 

The  only  direct  indication  that  we  have  of  a  possible  formation 
of  uric  acid  by  synthesis  in  mammals  is  the  work  of  Wiener. 
This  author  found  ^  that  uric  acid  is  formed  in  the  autodigestion 
of  cut-up  ox  liver.  If  the  alcohol  extract  of  another  liver  be 
added,  more  uric  acid  is  formed  in  a  definite  length  of  time. 
Since  the  alcoholic  extract  does  not  contain  purin  bodies,  Wiener 
believed  that  he  had  an  indication  that  there  was  something 
in  the  alcoholic  extract  from  which  uric  acid  was  formed  by  a 
synthetic  process.  It  seems  possible  to  us,  however,  that  the  uric 
acid  may  be  formed  from  the  nucleoproteids  of  the  cell  nuclei  by 
the  oxidizing  action  of  something  in  the  liver.  The  alcoholic 
extract  of  another  liver  may  contain  something  which  simply 
hastens  the  oxidation  process.  In  the  dog  liver  there  is  no  uric 
acid  found  on  autodigestion,  possibly  because  it  is  further  oxi- 
dized to  allantoin. 

It  will  be  remembered  that  Salkowski^  long  ago  showed  that 
if  weighed  amounts  of  purin  bases  be  added  to  cut-up  spleens 
or  livers,  and  the  mixture  digested  with  blood  and  air,  an  oxida- 
tion of  the  bases  to  uric  acid  takes  place.  If  the  spleen  or  liver 
be  left  out  in  the  experiment,  the  oxidation  does  not  take  place. 
There  is  something  in  the  spleen  and  liver  necessary  to  carry  on 
the  process. 

The  action  of  spleen,  liver,  and  other  organs  in  the  transforma- 
tion of  purin  bases  to  uric  acid  has  been  much  studied  recently. 
It  will  be  remembered  that  in  the  study  of  the  occurrence  of 
purin  bases  in  the  tissues,  we  saw  that  different  purin  bases  were 
obtained  in  fresh  organs  from  those  obtained  in  organs  which 
had  undergone  self -digestion.  The  results  of  Levene,^  who 
studied  this  subject,  show  that  the  amino  purins  change  to  the 
oxypurins  in  the  process  of  autolysis.  According  to  Jones,*  there 
is  an  enzyme  in  thymus  which  can  decompose  the  nucleoproteid 
and  give  the  free  amino  purins,  and  another  enzyme  which  changes 
the   amino  purins  to  the  oxypurins.     In  pancreas  there  is  an 

1  H.  Wiener.  Ueber  Zersetzung  und  Neubildiing  der  Harnsaure  im  Tierkorper.  Ver- 
handl.  des  18t  Kongr.  fiir  innere  Med.,  622  (1899),  and  Arch,  fiir  exp.  Path.  u.  Pharmak., 
42.  375   (1899). 

'  E.  Salkowski.  Ueber  Autodigestion  der  Organs.  Zeitschr.  fiir  klin.  Medizin,  17. 
Suppl.  77    (1890). 

5  P.  Levene.  The  Autolysis  of  Animal  Organs.  II.  Hydrolysis  of  Fresh  and  Self- 
digested  Glands.     Am.  Journ.  of  Physiol.,  12,  276  (1904). 

^  W.  Jones.  Uber  das  Enzyme  der  Thymusdriise.  Zeitschr.  fiir  physiol.  Chem., 
41,  101    (1904). 


182      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

enzyme  which  changes  the  guanin  to  xanthin.^  In  the  spleen 
there  is  an  enzyme  which  changes  adenin  to  hypoxanthin.^ 
According  to  Jones  "  guanase/'  the  ferment  which  changes 
guanin  to  xanthin,  is  a  different  body  from  "  adenase/'  which 
changes  adenin  to  hypoxanthin,  for  in  the  hver  the  adenin 
changes  to  hypoxanthin,  but  the  guanin  does  not  change  to 
xanthin.2  Schenk  ^  agrees  with  Jones  that  the  guanase  and 
adenase  are  different  ferments,  but  he  differed  from  Jones  in 
finding  an  adenase  but  not  guanase  in  pancreas.  The  view  of 
Schittenhelm^  seems  more  probable.  According  to  this  author, 
there  is  one  ferment  which  splits  the  purin  bases  from  nucleic 
acid;  another  which  changes  the  amino  purins  to  the  oxypurins, 
and  a  third  which  oxidizes  hypoxanthin  and  xanthin  to  uric  acid. 
These  ferments  are  widely  distributed  in  the  various  organs,  liver, 
spleen,  lungs,  and  muscle.  Schittenhelm  *  isolated  both  the 
oxidase  and  the  ferment  which  splits  off  the  amino  group  to  some 
extent.  These  ferments  do  not  act  on  the  nucleic  acid.  This 
author  believes  that  the  ferment  which  changes  the  amino 
purins  to  the  oxypurins  is  the  "  desamidierende  "  enzyme  which 
Lang  ^  has  found  widely  distributed  in  the  organism.  Burian  ^  like- 
wise has  found  in  organs  an  enzyme  which  oxidizes  oxypurins 
to  uric  acid. 

By  the  addition  of  tartronic  acid, 

COOH 

1 
CHOH 

COOH 

1  W.  Jones  und  C.  Partridge.  Uber  die  Guanase.  Zeitschr.  fiir  physiol.  Chem.,  42, 
343  (1904). 

2W.  Jones  und  M.  Winternitz.  Uber  die  Adenase.  Zeitschr.  fiir  physiol.  Chem.,  44, 
1  (1905). 

2  M.  Schenk.  Die  bei  der  Selbstverdauung  des  Pankreas  auftretenden  Nukleinbasen. 
Zeitschr.  fiir  physiol.  Chem.,  43,  406  (1905). 

*  A.  Schittenhelm.  Ueber  die  Harnsaurebildung  in  Gewebsausziigen.  Zeitschr.  fiir 
physiol.  Chem.,  42,  251  (1904). 

Ueber  die  Fermente  des  Nukleinstoffwechsels.  Zeitschr.  fiir  physiol.  Chem.,  43,  228 
(1904). 

^  S.  Lang.  Ueber  Desamidierung  im  Tierkorper.  Hofmeister's  Beitrage,  5,  321 
(1904). 

8  R.  Burian.  Die  Bildung  der  Harnsaure  im  Organismus  des  Menschen.  Med.  Klinik, 
1,  131   (1905). 

Ueber  die  Oxydative  und  die  vermeintUche  synthetische  Bildung  von  Harnsaure  in 
Einderleberauzug.     Zeitschr.  fiir  physiol.  Chem.,  43,  497  (1905). 

Die  Herkunft  der  endogenen  Harnpurine  bei  Mensch  Tind  Saugethiere.  Zeitschr.  fiir 
physiol.  Chem.,  43,  532  (1905). 


Physiology  183 

or  its  monoureidc,  dialurie  acid, 

XH  —  CO 

CO       CHOH 

NH  — CO 

to  a  quantity  of  cut-up  ox  liver,  and  subjecting  the  mass  to  auto- 
digestion  for  four  hours,  in  Wiener's  experiments,  a  shghtly 
larger  quantity  of  uric  acid  was  formed  than  when  the  tartronic 
acid  or  dialurie  acid  were  left  out.  The  addition  of  other  similar 
bodies,  such  as  malonic  acid,  barbituric  acid,  and  glycerin,  had  no 
effect. 

Wiener  supposed  that  uric  acid  was  synthesized  from  the  tar- 
tronic acid  and  the  dialurie  acid,  but  Burian^  has  explained 
Wiener's  results  in  another  way,  namely,  that  these  bodies 
merely  increase  the  rate  at  which  the  purin  bases  in  the  organ 
are  changed  to  uric  acid.  Burian  found  that  if  the  liver  is  first 
freed  in  large  part  from  the  purin  bodies,  and  then  allowed  to 
undergo  self-digestion,  no  uric  acid  is  formed,  even  when  tartronic 
acid  or  dialurie  acid  is  added.  When  xanthin  was  added  to  the 
liver,  uric  acid  was  formed,  and  the  rate  of  oxidation  of  xanthin 
to  uric  acid  was  increased,  when  dialurie  acid  or  tartronic  acid  was 
added.  Salicylic  acid  likewise  hastened  the  reaction.  Wiener  ^ 
found  that  the  administration  per  os  of  exceedingly  large  quan- 
tities (10  grams  to  15  grams)  of  dialurie  acid,  malonic  acid,  and 
lactic  acid  gave  an  exceedingly  slight  increase  in  the  excretion  of 
uric  acid  in  man.  The  increased  excretion  is  so  slight  as  to  seem 
but  a  doubtful  confirmation  of  Wiener's  views. 

We  have  already  seen  that  we  can  vary  the  food  in  calories, 
proteid,  fats,  and  carbohydrates  without  affecting  the  excretion 
of  uric  acid,  provided  the  amount  of  purin  bodies  in  the  food  is 
not  varied.  Fats  do  not  increase  the  excretion  of  uric  acid, 
according   to   the   experiments   of   Horbaczewski   and   Kanera,^ 

1  R.  Burian.  Die  Bildung  der  Harnsaure  im  Organismus  des  Menschen.  Med.  Kliiiik, 
1,  131  (1905). 

Ihid.  Ueber  die  oxydative  und  die  vermeintliche  synthetisehe  Bildung  von  Harnsaure 
in  Pdnderleberauszug.     Zeitschr.  fiir  physiol.  Chem.,  43,  497  (1905). 

2  H.  Wiener.  Ueber  Zersetzung  und  NeubUdung  der  Harnsaure  im  Tierkorper.  Ver- 
handl.  des  18t  Kongr.  fiir  innere  Med.,  622  1(1899),  and  Arch,  fiir  exp.  Path.  u.  Pharmak., 
42,  375  (1899). 

3  Horbaczewski  und  Kan^ra.  Ueber  den  Einfluss  von  Glycerin,  Zucker.  und  Fett  auf 
die  Ausscheidung  der  Harnsaure  beim  Menschen.  Sitzimgsber.  d.  kaiserl.  Akad.  d.  Wis- 
sensch.  zu  Wien.,  93,  2  Abth.,  583  (1886),  and  Monatshefte  fur  Chemie,  7,  105  (1886). 


184      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Herrmann/  Kaiifmann  and  Mohr,^  and  Laquer.^  The  experiments 
of  Horbaczewski  and  Kanera/  Weiss ,^  and  Kaufmann  and  Mohr  ^ 
show  that  carbohydrates  hkewise  have  no  effect. 

Only  Meissner  ^  and  Rosenfeld  and  Orgler  '^  find  that  carbo- 
hydrates or  fats  increase  the  excretion  of  uric  acid,  and  their 
work  is  open  to  criticism. 

Meissner  used  dogs  in  his  experiments  and  used  an  inaccurate 
method  for  determining  uric  acid.  It  is  on  the  work  of  Meissner 
that  the  idea  is  based  of  forbidding  the  use  of  fats  in  the  uric  acid 
diathesis.  It  may  be  noted  that  in  accord  with  the  old  view  that 
uric  acid  is  a  product  of  incomplete  oxidation,  Meissner  stated 
that  the  body  has  only  a  certain  amount  of  oxygen  at  its  disposal, 
and  that  if  large  quantities  of  fats  are  administered,  the  supply 
of  oxygen  will  be  largely  used  by  them,  and  there  will  be  insuffi- 
cient oxygen  to  oxidize  the  uric  acid  to  urea. 

Rosenfeld  and  Orgler^  found  a  greater  excretion  of  uric  acid 
on  a  diet  containing  600  grams  of  meat  than  on  one  containing 
800  grams  meat,  a  fact  which  indicates  that  their  work  is 
of  doubtful  value.  Again,  in  an  experiment  lasting  four  days, 
during  which  time  600  grams  meat  per  day  was  taken,  1.005 
grams  uric  acid  was  excreted  the  first  day,  .772  gram  the  second, 
.576  gram  the  third,  and  .934  gram  the  fourth.  Either  the 
food  on  these  days  contained  varying  amounts  of  purin  bodies, 
the  analyses  are  incorrect,  or  the  patient  was  not  in  a  normal 
healthy  condition.  The  daily  variation  of  excretion  is  far  too 
great  for  a  fixed  diet.     On   two   following  days,  150  grams   of 

1  A.  Herrmann.  Ueber  die  Abhangigheit  der  Harnsaureausscheidung  von  Nahrungs 
und  Genussmitteln  mit  Riicksicht  auf  die  Gicht.  Dtsch.  Arch,  fiir  klin.  Med.,  43, 
273  (1888). 

2  M.  Kaufmann  iind  L.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologic 
der  Gicht.     Dtsch.  Arch,  fiir  klin.  Med.,  74,  141  (1902). 

3  B.  Laquer.  Ueber  die  Beeinfiussung  der  AUoxurkorper  (Harnsaure  +  Xanthin- 
basen)-  Ausscheidung  duroh  Milchdiat  und  iiber  Fettmilch  bei  Gicht.  Berl.  kUn.  Wo- 
chenschrift,  32,  807  (1896). 

*  Horbaczewski  und  Kanera.  Ueber  den  Einfluss  von  Glycerin,  Zucker  und  Fett  auf 
die  Ausscheidung  der  Harnsaure  beim  Menschen.  Sitzungsber.  d.  kaiserl.  Akad.  d.  Wis- 
sensch.  zu  Wien.,  93,  2  Abth.,  583  (1886),  and  Monatshefte  fiir  Chemie,  7,  105  (1886). 

■''  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fiir  physiol.  Chem.,  25,  393  (1898). 

0  G.  Meissner.  Ueber  das  Entstehen  der  Bernsteinsaure  im  thierischen  Stoffwechsel. 
Zeitschr.  fiir  rationelle  Med.,  24,  97,  1865. 

"■  G.  Rosenfeld  und  Orgler.  Zur  Behandlung  der  harnsauren  Diathese.  Centralblatt 
fiir  innere  Medizin,  17,  42  (1896). 

G.  Rosenfeld.  Grundzuge  der  Berhandlung  der  harnsauren  Diathese.  Verhandl.  des 
14t  Kongr.  fiir  innere  Med.,  321  (1896). 

Harnsaure  und  Diate.     Allgem.  medicinische  Centralzeitung,  65,  789  (1896). 


Physiology  185 

butter  were  added  to  the  diet,  and  1.003  grams  uric  acid  was 
excreted  on  one  day  and  .785  gram  on  the  next.  On  two  con- 
secutive days,  during  which  the  diet  consisted  of  800  grams  meat 
and  150  grams  butter,  the  excretion  of  uric  acid  was,  respect- 
ively, 1.202  grams  and  .694  gram.  In  these  experiments  again 
the  variations  in  the  amounts  of  uric  acid  excreted,  when  the 
diet  was  fixed,  are  greater  than  can  be  accounted  for  on  the  as- 
sumption that  the  patient  is  normal  and  the  purin  content  of 
the  food  constant. 

From  Burian  and  Schur  ^  we  get  evidence  which  seems  to  indi- 
cate pretty  clearly  that  if  uric  acid  can  be  formed  synthetically 
in  mammals,  that  which  is  so  formed  is  not,  as  in  birds,  affected 
by  the  quality  or  the  quantity  of  the  diet.  In  a  series  of  experiments 
of  their  own  and  of  Kriiger  and  Schmidt,  Loewi,  and  Horbac- 
zewski,  in  which  the  quality  and  quantity  of  the  diet  was  of  the 
most  varied  character  in  the  different  experiments,  they  com- 
pared the  amount  of  uric  acid  actually  excreted  with  the  amount 
they  calculated  should  be  excreted,  assuming  that  all  the  exoge- 
nous uric  acid  comes  from  the  purin  bodies  of  the  food.  In 
their  experiments  they  assumed  that  52  per  cent  of  the  hypo- 
xanthin  of  the  food  is  excreted  as  uric  acid.  The  results  obtained 
by  calculation  agreed  remarkably  closely  with  the  results  obtained 
by  analysis,  showing  that  if  compounds  in  the  food  other  than 
the  purin  bodies  can  influence  the  excretion  of  uric  acid,  the  influ- 
ence is  insignificant. 

Siven-  as  a  result  of  his  work,  came  to  a  conclusion  identical 
with  that  of  Burian  and  Schur,  namely,  that  the  foodstuffs  other 
than  purin  bodies  have  no  influence  on  the  excretion  of  uric  acid. 

To  summarize  briefly  the  results  we  may  say  that  there  is  no 
positive  experimental  evidence  at  present  to  show  that  uric  acid  can 
be  synthesized  in  the  mammal  organism.  Since  nothing  in  food- 
stuffs free  from  purin  bodies  has  any  apparent  effect  on  the  excre- 
tion of  uric  acid,  we  must  assume  that  there  is  nothing  in  our  food  or 
the  decomposition  products  of  our  food  from  which  uric  acid  can 
be  synthesized.  We  have  not  yet  enough  data  concerning  the 
formation  of  uric  acid  in  muscular  activity  to  give  an  explana- 
tion, but  it  may  be  possible  that  this  is  due  to  some  sort  of  syn- 

'  R.  Burian  und  H.  Schur.  Das  quantitativen  Verhalten  der  menschlichen  Harnpurin- 
ausscheidung.     Pfltiger's  Archiv,  94,  273  (1903). 

2  v.  Siven.  Zur  Kenntniss  der  Harnsaurebildung  im  menschlichen  Organismus  unter 
physiologischen  Verhaltnissen.     Skand.  Arch.  f.  Physiol.,  11,  123  (1901). 


186      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

thetic  process,  perhaps  analogous  somewhat  to  the  synthesis  of 
nucleoproteid  in  the  organism. 

The  Decomposition  of  Uric  Acid  in  the  Body 

The  old  view  of  the  significance  of  uric  acid  in  metabolism, 
as  we  have  already  seen,  was  that  uric  acid  is  an  intermediate 
product  in  the  oxidation  of  proteid  matter  to  urea.  This  view, 
which  is  expressed  in  the  textbook  of  Liebig,^  was  based  on  the 
fact  that  outside  the  body  uric  acid  is  easily  oxidized  to  urea,  and, 
further,  on  the  fact  that  Frerichs  and  Wohler  ^  fed  uric  acid  to 
rabbits  and  dogs,  but  did  not  find  it  again  in  the  urine.  They  did 
find,  however,  an  increased  excretion  of  urea.  According  to 
this  theory,  the  presence  of  uric  acid  in  the  urine  is  due  to  insuffi- 
cient oxidation.  The  more  complete  the  process  of  oxidation, 
the  less  uric  acid  is  found  in  the  urine. 

Even  after  Liebig's  theory  was  shown  to  be  incorrect,  and  it 
was  found  that  the  metabolism  of  proteid  and  the  metabolism 
of  uric  acid  are  quite  independent,  the  idea  prevailed  for  a  long 
time  that  uric  acid  is  destroyed  by  the  animal  organism,  and  that 
the  uric  acid  found  in  the  urine  is  but  a  small  part  of  the  uric  acid 
at  one  time  present  in  the  body.  In  fact,  it  is  only  recently  that 
the  work  has  been  done  which  indicates  that  in  man  a  consid- 
erable part  of  the  uric  acid  formed  in  the  body  is  excreted  un- 
changed. In  different  classes  of  animals  the  fraction  excreted 
unchanged  is  different.  The  products  of  oxidation  of  uric  acid 
in  different  classes  of  mammals  seem  to  be  different,  but  this 
cannot  yet  be  considered  as  definitely  settled. 

The  fact  that  only  a  part  of  the  uric  acid  corresponding  to  the 
purin  bodies  in  the  food  is  excreted  has  been  explained  in  different 
ways.  Garrod  and  certain  others  have  maintained  that  an 
explanation  is  afforded  if  we  assume  that  uric  acid  is  formed  in 
the  kidneys.  According  to  Kolisch  and  Dostal,^  we  have  a  proof 
of  this  theory  in  their  experiments.  They  showed  that  in  kidney 
diseases  the  excretion  of  uric  acid  is  decreased,  and  the  excretion 

1  J.  Liebig.  Animal  Chemistry,  or  Organic  Chemistry  in  its  Application  to  Physiology 
and  Pathology.     Transl.  by  W.  Gregory.     Ed.  by  J.  Webster  (1843). 

2  F.  Frerichs  und  F.  Wohler.  Ueber  Veranderungen  welche  namentlich  organische 
Stoffe  bei  ihrem  Uebergang  in  der  Harn  erleiden.  Liebig's  Ann.  der  Chem.  u.  Pharm.,  65 
335  (1848). 

3  R.  Kolisch  und  H.  Dostal.  Das  Verhalten  der  Alloxurkorper  im  pathologischen  Harn. 
Wien  kUn.  Wochenschrift,  8,  435  (1895). 


Physiology  187 

of  purin  bodies  increased.  These  authors,  however,  used  the 
inaccurate  Kriiger-Wulff  method  for  determining  the  purin  bodies 
in  urine.  We  shall  see  later  that  uric  acid  is  not  formed  in  the 
kidneys. 

The  explanation  offered  by  Liithje  ^  seems  satisfactory.  Purin 
bases  and  uric  acid  are  bodies  which  can  be  excreted.  A  part  of 
the  blood  has  been  freed  from  purin  bodies  before  reaching  the 
kidneys.  The  rest  of  the  blood  contains  a  certain  amount  of 
purin  bodies  and  these  are  excreted.  Burian  and  Schur  ^  think 
that  their  work  confirms  this  view,  in  dogs  at  any  rate.  By  in- 
creasing the  blood  supply  of  the  kidneys  of  dogs  through  the 
action  of  diuretics,  without  at  the  same  time  affecting  the  blood 
supply  of  the  liver,  which  organ,  in  dogs,  as  we  shall  see,  destroys 
uric  acid,  they  increased  the  excretion  of  uric  acid. 

Another  point  to  be  considered  in  a  study  of  the  decomposition 
of  uric  acid  in  the  body  is  that  sometimes  concretions  of  uric 
acid  may  be  stored  up  in  certain  parts  of  the  body.  In  such 
cases  the  amount  of  uric  acid  in  the  urine  cannot  be  considered 
a  measure  of  the  amount  of  uric  acid  formed.  It  will  be  seen, 
however,  that  normally  such  a  retention  of  uric  acid  does  not 
occur.  The  importance  of  a  consideration  of  the  decomposition 
of  uric  acid  in  the  body  in  general  and  the  retention  of  uric  acid 
in  particular  will  be  seen  when  we  reach  the  subject  of  gout. 

DECOMPOSITION  PRODUCTS  OF  URIC  ACID  OUTSIDE  THE  BODY 

By  the  action  of  different  agents,  uric  acid  undergoes  decompo- 
sition in  a  number  of  different  ways.  There  are  three  methods 
of  decomposition  which  give  products  found  in  the  animal  body, 
and  which,  therefore,  have  been  considered  physiologically  im- 
portant by  different  authors. 

1.  By  the  action  of  nitric  acid,  alloxan  and  urea  are  formed. 
On  warming,  the  alloxan  decomposes  further  to  parabanic  acid, 
then  to  oxaluric  acid,  and  finally  to  oxalic  acid.  According  to 
Salkowski,^  oxalic  acid  and  urea  are  formed  directly  from  uric 
acid  by  the  action  of  FeClg. 

2.  By  the  action  of  potassium  permanganate,  uric  acid  de- 

1  H.  Liithje.  Der  heutige  Stand  der  Alloxurkorperfrage.  Arch,  fiir  Verdauungskrank- 
heiten,  2,  345  (1896). 

-  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  StofE- 
wechsel.     2.  Mitth.     Pfliiger's  Archiv,  87,  239  (1901). 

'  E.  Salkowski.     Beitrage  zur  Chemie  des  Hams.     Pfliiger's  Archiv,  2,  351  (1869). 


188      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

composes  to  allantoin.  On  further  oxidation,  the  allantoin  de- 
composes to  oxahc  acid  and  urea. 

3.  When  uric  acid  is  heated  with  hydriodic  acid  in  a  sealed 
tube,  glycocoU,  ammonia,  and  carbonic  acid  are  formed. 

Carbon  dioxide,  ammonia,  urea,  glycocoll,  allantoin,  and  oxalic 
acid  are  all  found  in  the  mammal  organism. 

IN  RABBITS 

Early  Work 

Wohler  and  Frerichs^  performed  four  experiments  on  rab- 
bits, in  which  they  fed  in  each  case  2.5  grams  potassium  urate. 
They  found  an  increased  excretion  of  urea,  and  a  sediment 
of  calcium  oxalate  in  the  urine,  but  no  sediment  of  uric 
acid  or  urates.  They  assumed  that  the  uric  acid  had  been 
oxidized  to  allantoin  and  then  to  urea  and  oxalic  acid.  Neu- 
bauer  ^  fed  24  grams  uric  acid  to  a  rabbit.  He  found  that  there 
occurred  an  increased  excretion  of  15.95  grams  urea.  Theoreti- 
cally, 17.13  grams  urea  can  be  obtained  from  24  grams  uric  acid. 
Neubauer  found  a  small  amount  of  uric  acid  in  the  urine,  but  no 
considerable  amount  of  oxalates.  When  uric  acid  was  adminis- 
tered at  night,  he  found  a  sediment  of  oxalates  in  the  urine  the 
next  morning.  According  to  Neubauer,  the  presence  of  the  oxalates 
is  due  to  the  fact  that  the  oxidation  processes  are  retarded  at 
night,  and  that,  therefore,  the  uric  acid  is  not  oxidized  completely 
to  carbon  dioxide  and  urea. 

At  the  time  of  Wohler  and  Frerichs  and  Neubauer,  there  was 
no  accurate  method  in  use  for  the  quantitative  determination 
of  urea.  Liebig's  method,  which  was  the  method  used,  gives  the 
creatin,  uric  acid,  and  other  nitrogenous  bodies  as  well  as  urea. 
The  formation  of  a  sediment  of  oxalates  in  the  urine,  like  the 
formation  of  a  sediment  of  urates,  is  determined,  not  altogether 
by  the  amount  present,  but  also  by  the  reaction  of  the  urine,  and 
by  the  amounts  of  other  bodies  present.^  The  observations  of 
Wohler  and   Frerichs  and  Neubauer  are,  therefore,  worthless. 

1  F.  Wohler  und  F.  PYerichs.  Ueber  Veranderungen,  welche  namentlich  organisch 
Stoffe  bei  ihrem  Uebergang  in  den  Ham  erfahren.  Ann.  d.  Chem.  u.  Pharm.,  65,  335 
(1848). 

2  C.  Neubauer.  Ueber  die  Zersetzung  der  Harnsaure  im  Tierkorper.  Ann.  der  Chem.  u. 
Pharm.,  99,  206  (1856). 

3/6td.    Arch.  f.  wissensch.  Heilk.  (1858),  1. 


Physiology  189 

Absorption  and  Excretion  as  Uric  Acid  or  Urea 

Burian  and  Schur  ^  found  that  17.7  per  cent  of  the  uric  acid 
injected  into  a  rabbit  is  excreted  unchanged.  About  the  same 
fraction  of  the  hypoxanthin  injected  is  found  as  uric  acid  in  the 
urine. 

Croftan^  performed  experiments  which  showed  directly  that 
some  of  the  uric  acid  fed  to  rabbits  is  excreted  unchanged.  He 
injected  uric  acid  into  rabbits  and  found  from  11  to  17  per  cent 
unchanged  in  the  urine.  None  was  found  in  the  feces,  in  the 
blood,  or  in  the  internal  organs.  He  concluded  that  the  other 
83  to  89  per  cent  must  have  been  destroyed. 

According  to  Bendix  and  Schittenhelm,^  very  little  of  the  uric 
acid  taken  in  the  food  is  excreted  unchanged,  but  when  it  is  given 
subcutaneously  or  intravenously,  a  large  part  is  excreted  un- 
changed. 

Salkowski  *  has  attempted  to  determine  the  amount  of  uric 
acid  absorbed  by  rabbits,  and  its  fate  in  the  body.  This  author 
determined  the  total  nitrogen,  the  urea,  and  the  total  sulphur, 
and  in  one  case  also  the  uric  acid,  in  the  urine  of  rabbits  fed  on 
a  fixed  diet.  He  then  added  uric  acid  to  the  food  and  found  that 
the  excretion  of  total  nitrogen  and  urea  was  increased.  The 
excretion  of  sulphur  was  not  increased.  The  increased  excretion 
of  nitrogen,  therefore,  was  due  to  an  absorption  of  the  uric  acid 
and  not  to  increased  decomposition  of  body  proteid,  since  the 
ratio  N  :  S  in  the  urine  is  nearly  constant  where  there  is  simply 
a  variation  in  the  proteid  metabolism.  In  this  way  Salkowski 
found  that  a  variable  part  of  the  uric  acid,  from  one  half  to  the 
whole,  is  absorbed  and  excreted,  mostly  as  urea.  A  small  part  is 
excreted  as  uric  acid,  and  probably,  according  to  Salkowski,  a 
small  part  as  allantoin. 

That  some  uric  acid  can  escape  oxidation  in  rabbits  is  indicated 
by  the  fact  that  Ebstein  and  Nikolaier^  found  snaall  crystals  of 

1  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen 
Stoffwechsel.     2.  Mitth.     Pfliiger's  Archiv,  87,  239  (1901). 

2  A.  Croftan.  Synopsis  of  experiments  on  the  transformation  of  circulating  uric  acid 
in  the  organism  of  man  and  animals.     Med.  Record,  64,  16  (1903). 

^  E.  Bendix  und  A.  Schittenhelm.  Ueber  die  Ausscheidungsgrosse  per  os,  subcutan 
und  intravenos  eingefiihrten  Harnsaure  beim  Kaninchen.  Zeitschr.  fiir  physiol.  Chem., 
42,  461    (1904). 

*  E.  Salkowski.  Ueber  das  Verhalten  in  den  Magen  eingefiihrter  Harnsaure  im  Organ- 
ismus.     Zeitschr.  fiir  physiol.  Chem.,  35,  495  (1900). 

^  W.  Ebstein  und  A.  Nikolaier.  Ueber  die  Ausscheidung  der  Harnsaure  durch  die 
Niere.     Virchow's  Archiv,  143,  337  (1896). 


190      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

uric  acid  in  the  kidneys  after  subcutaneous,  intravenous,  and 
intraperitoneal  injections  of  uric  acid. 

Oxidation  to  Allantoin,  Oxalic  Acid,  Oxaluric  Acid,  Alloxan, 
Alloxantin,  and  Parahanic  Acid 

Administration  of  uric  acid  probably  does  not  increase  the 
excretion  of  allantoin.  Salkowski  did  not  find  allantoin  in  the 
urine  by  direct  experiment  after  feeding  uric  acid  to  rabbits,  nor 
did  Mendel  and  White,^  who  introduced  uric  acid  and  urates 
intravenously.  It  is  probable  that  in  this  animal  allantoin  is 
almost  completely  oxidized. 

Luzzato^  did  not  find  allantoin  in  the  urine  of  rabbits  after 
feeding  allantoin  to  them.  He  did  find,  however,  that  the  oxalic 
acid  in  the  urine  was  very  largely  increased.  In  an  experiment 
in  which  about  3  grams  allantoin  were  fed,  and  about  1.5  grams 
absorbed,  the  excretion  of  oxalic  acid  was  increased  by  about 
.0438  gram.  According  to  Hildebrandt,^  and  Autenrieth  and 
Barth,*  oxalic  acid  administered  per  os  does  not  reappear  in  the 
urine.  On  the  other  hand,  Hildebrandt^  found  that  about  10 
per  cent  of  the  sodium  oxalate  injected  subcutaneously  appears 
in  the  urine.  According  to  this,  the  .0438  gram  of  oxalic  acid 
found  in  the  urine  in  Luzzato's  experiment  represents  about 
.4380  gram  oxalic  acid  formed  in  the  body.  This  is  about  27 
per  cent  of  the  weight  of  the  allantoin  administered.  Accord- 
ing to  the  reaction  of  Glaus  ^  for  the  formation  of  oxalic  acid  from 
allantoin,  3C4H6N,03  +  ISHp  =  I2NH3  +  BCO^  +  2C2HA 
+  C2HP2  +  2H2O,  the  weight  of  oxalic  acid  formed  is  about 
38  per  cent  of  the  allantoin  decomposed.  If,  then,  allantoin 
were  formed  by  the  oxidation  of  uric  acid  in  the  organism  of  the 
rabbit,  it  is  probable  that  it  would  be  further  decomposed  in 
large  part  to  oxalic  acid. 

1  L.  Mendel  and  B.  White.  On  the  intermediary  metabolism  of  the  purin  bodies. 
The  formation  of  allantoin  in  the  animal  body.  Am.  Jonrn.  of  Physiol.,  12,  85 
(1904). 

2  A.  Luzzato.  Ueber  das  Verhalten  des  Allantoins  im  Tierkorper.  Zeitschr.  fiir 
physiol.  Chem.,  38,  537   (1903). 

3  H.  Hildebrandt.  Ueber  eine  experimentelle  Stoffwechselabnormitat.  Zeitschr.  fiir 
physiol.  Chem.,  35,  141  (1902). 

*  W.  Autenrieth  und  H.  Earth.  Ueber  Vorkommen  und  Bestimmung  der  Oxalsaurelim 
Ham.     Zeitschr.  fiir  physiol.  Chem.,  35,  327  (1902). 

"•  A.  Claus.  Zur  Kenntniss  der  Harnsauregruppe.  Ber.  der  Dtsch.  chem.  Gesell.,  7, 
226  (1874). 


Physiology  191 

Luzzato^  found  that  the  administration  of  uric  acid  per  os 
does  not  increase  the  excretion  of  oxalic  acid.  This  indicates 
that  the  theory  of  Neubauer  and  of  Wohler  and  Frerichs  is  in- 
correct. It  indicates,  also,  that  uric  acid  does  not  oxidize  to 
allantoin  in  the  rabbit,  since  the  allantoin,  as  we  have  seen, 
would  be  oxidized  further  to  oxalic  acid.  Luzzato  ^  found,  too, 
that  oxaluric  acid  oxidizes  to  oxalic  acid  in  the  rabbit,  so  that 
it  seems  improbable  that  any  oxaluric  acid  is  formed  by  the 
oxidation  of  uric  acid.  Lusini  ^  found  that  alloxan,  alloxantin, 
and  parabanic  acid  are  toxic  to  rabbits  in  very  small  quantities, 
so  that  these  are  probably  not  formed  by  the  oxidation  of  uric 
acid. 

Oxidation  to  Glycocoll 

Wiener's  work  is  the  most  indicative  of  the  way  in  which 
uric  acid  is  oxidized  in  the  rabbit.^  Wiener  found  that  the 
toxic  dose  of  benzoic  acid  is  1.7  grams  per  kilo  of  rabbit. 
When  1  gram  benzoic  acid  is  administered,  it  combines  with 
glycocoll  and  gives  about  .83  gram  of  hippuric  acid.  When 
more  than  1  gram  benzoic  acid  is  given,  about  the  same 
amount  of  hippuric  acid  is  excreted.  The  excess  of  benzoic 
acid  is  passed  off  unchanged.  This  indicates  that  the  rabbit 
organism  is  able  to  furnish  a  maximum  of  about  .34  gram 
glycocoll  to  combine  with  benzoic  acid  to  form  hippuric  acid. 
When  glycocoll  is  administered  with  the  hippuric  acid,  this  gly- 
cocoll combines  with  some  benzoic  acid  to  form  hippuric  acid. 
There  is  then  more  hippuric  acid  and  less  free  benzoic  acid  ex- 
creted than  without  the  glycocoll.  The  fatal  dose  of  benzoic 
acid  is  thereby  raised  from  1.7  grams  to  2.39  grams  per  kilo. 
The  excretion  of  hippuric  acid  is  increased  from  .83  gram  to 
1.48  grams.  The  administration  of  uric  acid  with  the  benzoic 
acid  has  the  same  effect  as  the  administration  of  glycocoll.  The 
administration  of  .36  gram  uric  acid  increased  the  excretion  of 
hippuric  acid  from  .83  gram  to  about  1.14  grams  per  day  per 
kilo  of  rabbit,  and  enabled  rabbits  to  stand  a  dose  of  1.7  grams 

'  A.  Luzzato.  Zur  Physiologie  der  oxalsaure  und  oxalursaure  im  Ham.  Zeitschr.  fiir 
physiol.  Chem.,  37,  225  (1903). 

^  V.  Lusini.  Ueber  die  biologische  Wirkung  der  Ureide  mit  Beziehung  auf  ihre  chemische 
Konstitution.  1.  Alloxan,  Alloxantin,  und  Parabansaure.  Chem.  Centralbl.,  1,  1074 
(1895). 

'  H.  Wiener.  Ueber  das  Glycocoll  als  intermediares  Stoffwechselprodukt.  Arch,  fiir 
exp.  Path.  u.  Pharmak.,  40,  313  (1897). 


192      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

benzoic  acid  without  fatal  consequences.  This  indicates,  ac- 
cording to  Wiener,  that  in  the  rabbit  uric  icid  decomposes  with 
formation  of  glycocoll.  This  is  the  way  uric  acid  decomposes 
when  heated  with  hydrochloric  acid. 

Wiener  ^  does  not  believe  that  the  uric  acid  decomposes  first 
to  allantoin  or  hyantoin  and  then  to  glycocoll,  for  in  a  later  ar- 
ticle, he  showed  that  1.7  grams  benzoic  acid  is  still  poisonous  to 
a  rabbit  after  administration  of  hyantoin  or  allantoin.  Neither 
does  he  think  that  uroxanic  acid  is  an  intermediate  oxidation 
product  between  uric  acid  and  glycocoll,  since  Sundwik  showed 
that  uroxanic  acid  cannot  decrease  the  poisonous  action  of 
benzoic  acid.  Nor  does  he  think  that  the  uric  acid  decomposes 
first  to  alloxan  and  this  later  to  glycocoll  and  parabanic  acid, 
for  alloxan  and  parabanic  acid  are  poisonous,  according  to  both 
Wiener  and  Lusini.^ 

Burian  and  Schur^  state  that  it  is  possible  that  the  uric  acid 
administered  to  rabbits  may  increase  the  formation  of  glycocoll 
without  necessarily  changing  into  glycocoll.  Cohn  *  and  Wiener  ^ 
have  since  indulged  in  a  polemic  over  the  whole  question  of  the 
glycocoll  formation  in  the  body  without  being  able  to  come  to 
an  agreement. 

Wiener  performed  but  three  experiments  in  uric  acid  feeding. 
In  these  experiments  the  average  increase  in  the  excretion  of 
hippuric  acid  after  uric  acid  feeding  was  more  than  could  be  ac- 
counted for  by  assuming  that  the  uric  acid  was  quantitatively 
changed  to  glycocoll  according  to  the  reaction.  This  may  be  due 
to  experimental  errors,  but,  at  any  rate,  Wiener's  work  needs 
confirmation  in  some  way  before  we  can  accept  his  conclusions 
as  definitely  proved. 

Summary 
To  sum  up,  then,  it  seems  probable  that  in  the  rabbit  uric  acid 
is  absorbed  in  variable  quantities  when   administered   per  os. 

1  H.  Wiener.  Ueber  Zersetzung  und  Neubildung  der  Harnsaure  im  Thierkorper.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  42,  375  (1899),  and  Verhandl.  des  17t  Kongr.  fur  innere  Med., 
622  (1899). 

2  V.  Lusini.  Ueber  die  biodogische  Wirkung  des  Ureide  mit  Beziehung  auf  ihre  chem- 
ische  Konstitution.  1.  Alloxan,  AUoxantin,  und  Parabansaure.  Chem.  Centralbl.,  1, 
1074  (1895). 

3  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschUchen  Stoff- 
wechsel.     2.  Mitth.     Pfliiger's  Archiv,  87,  239  (1901). 

*  R.  Cohn.  Zur  Frage  des  Glykokolvorraths  im  thierischen  Organismus.  Prager 
mediz.  Woehenschrift,  27,  269,  und  287  (1902). 

^  H.  Wiener.  Zur  Frage  des  Glykokolvorraths  im  thierischen  Organismus.  Prager 
mediz.  Woehenschrift,  27,  290  (1902). 


Physiology  193 

The  amount  of  the  uric  acid  absorbed  which  is  excreted  unchanged 
is  very  small  according  to  Salkowski,  about  17  per  cent  accord- 
ing to  Burian  and  Schiir,  and  11  to  17  per  cent  according  to 
Crofton.  The  uric  acid  decomposes,  giving  giycocoll  according 
to  Wiener,  and  urea  according  to  Salkowski.  It  may,  of  course, 
be  true  that  the  uric  acid  decomposes  first  to  giycocoll  and  then 
to  urea,  or  into  both  giycocoll  and  urea.  Tt  seems  improbable 
that  more  than  very  small  amounts  of  allantoin,  alloxan,  oxalic 
acid,  parabanic  acid,  uroxanic  acid,  or  alloxantin  are  formed 
either  as  intermediate,  or  as  end  products. 

DOGS  AND  CATS 

Early  Work 

Gallois  ^  fed  potassium  urate  to  dogs,  but  did  not  find  that 
it  gave  increased  excretion  of  urea.  Zabelin-  fed  44  grams 
uric  acid  to  two  dogs  in  the  course  of  several  weeks  and 
found  that  it  was  almost  all  excreted  as  urea.  These  au- 
thors, however,  determined  urea  by  Liebig's  method,  —  pre- 
cipitation with  nitrate  of  mercury  and  determination  of  nitrogen 
in  the  precipitate.  This  gives  the  sum  of  the  urea,  uric  acid, 
hippuric  acid,  purin  bases,  creatin,  and  other  nitrogenous  bodies. 
Zabelin's  results  are,  therefore,  worthless,  and  probably  also 
those  of  Gallois. 

Absorption  and  Excretion  as  Uric  Acid  and  Urea 

Salkowski  ^  found  by  the  same  method  of  experiment  that  he 
used  in  the  case  of  rabbits  that  a  variable  part,  from  20  to  50  per 
cent,  of  the  uric  acid  administered  was  absorbed.  Of  this,  a  part 
was  excreted  as  urea.  That  the  dog  can  excrete  a  considerable 
quantity  of  uric  acid,  either  oxidized  or  unoxidized,  is  shown  by 
the  fact  that  Ebstein  and  Nikolaier  ^  observed  no  evil  effects  on  a 
dog  and  no  concretions  of  uric  acid  in  the  kidneys  when  10  grams 
uric  acid  per  day  were  fed  to  it  for  five  and  one-half  months. 

In    Zabelin's    experiment  there    was  a  slight  increase  in  the 

1  Gallois.     Experiences  sur  Furfe  et  las  urates.     Comptes  rendus,  44,  734  (1857). 

2  Zabelin.  Ueber  die  Umwandlung  der  Harnsiiure  im  Thierkorper.  Ann.  d.  Chem. 
u.  Pharm.,  2  SiippL,  326  (1863). 

3  E.  Salkowski.  Ueber  das  Verhalten  in  den  Magen  eingefuhrter  Harnsiiure  im  Organ- 
ismus.     Zeitschr.  fiir  physiol.  Chem.,  35,  495  (1902). 

*  W.  Ebstein  und  A.  Nikolaier.  Ueber  die  Ausscheidung  der  Ilarnsaure  durch  die 
Niere.     Virchow's  Archiv,   143,  337  (1896). 


194      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

excretion  of  uric  acid  after  feeding  uric  acid.  Meissner^  also 
found  a  slightly  increased  excretion  of  uric  acid  after  feeding 
1  gram  sodium  urate  to  a  dog.  Salkowski  ^  fed  4  grams  of  uric 
acid  to  each  of  two  dogs  in  two  days,  but  did  not  observe  an  in- 
creased excretion  of  uric  acid. 

Swain  ^  found  from  2  to  3  per  cent  of  the  uric  acid  adminis- 
tered to  dogs  excreted  unchanged.  Burian  and  Schur^  found 
that  from  4  to  5  per  cent  of  the  uric  acid  injected  into  dogs  is 
excreted  unchanged.  This  same  fraction  of  the  purin  bodies 
administered  is  excreted  as  uric  acid  whether  it  be  given  as  uric 
acid,  hypoxanthin,  or  thymus,  and  whether  it  be  given  per  os 
or  injected.  In  one  of  the  dogs  used  the  fraction  excreted  was 
always  12  per  cent. 

Minkowski  ^  also  found  that  about  4  per  cent  of  the  hypo- 
xanthin fed  is  excreted  as  uric  acid.  According  to  Spiegelberg,^ 
the  full-grown  dog  destroys  all  but  about  5.6  per  cent  of  the  uric 
acid  administered.  He  found  that  the  puppy  destroys  less, 
and  that  after  subcutaneous  administration  of  uric  acid  to  puppies 
concretions  of  uric  acid  are  found  in  the  kidneys.  Minkowski's 
experiments,^  too,  in  which  the  administration  of  nuclein  and 
thymus  gave  increased  excretion  of  uric  acid,  show  that  not  all 
the  uric  acid  formed  in  the  dog  is  oxidized. 

According  to  Kanger,^  when  uric  acid  is  administered  to  cats, 
there  is  an  increased  excretion  of  it,  corresponding  to  a  small  per 
cent  of  the  quantity  administered. 

According  to  Burian  and  Schur,*  the  endogenous  as  well  as 
the  exogenous  uric  acid  can  be  destroyed  by  the  organism  of  the 
dog  and  cat,  for,  after  kidney  extirpation,  there  is  no  uric  acid 
found  in  the  blood,  and  none  is  excreted  into  the  alimentary 
canal.     We  shall  see  later  that  the  liver  of  the  dog  oxidizes  uric 

1  G.  Meissner.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  tierischen  Organismus. 
Zeitschr.  fur  rationelle  Med.,  31,  3,  Reihe,  234  (1868). 

2  E.  Salkowski.  Bildung  von  Allantoin  aus  Harnsaure  im  Tierkorper.  Ber.  der  Dtsch. 
chem.  Gesell.,  9,  719  (1876). 

3  R.  E.  Swain.  The  Formation  of  Allantoin  from  Uric  Acid  in  the  Animal  Body.  Am. 
Journ.  of  Physiol.,  6,  38  (1901). 

*  A.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     2.  Mitth.     Pfliiger's  Archiv,  87,  239  (1901). 

s  O.  Minkowski.  Untersuchungen  zur  Physiologic  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fur  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

^  H.  Spiegelberg.  Ueber  den  Harnsaureeinfarct  der  Neugeborenen.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  41,  428  (1898). 

'  A.  Kanger.  Ueber  die  Moglichkeit  einer  Steigerung  der  Harnsaureausscheidung  bei 
Katzen  durch  Einfuhr  reiner  Harnsaure  per  os.     Pfliiger's  Archiv,  100,  428  (1903). 


Physiology  195 

acid.  If  the  liver  be  cut  out  of  the  circulation  by  tying  the  blood 
vessels  le'ading  to  and  from  it,  then  uric  acid  is  found  in  the  blood 
after  kidney  extirpation.  By  giving  diuretics,  which,  according 
to  these  authors,  increase  the  rate  at  which  blood  is  supplied  to 
the  kidneys,  a  greater  amount  of  uric  acid  escapes  oxidation  and 
is  excreted. 

Oxidation  to  Allantoin 

Allantoin  was  found  by  Frerichs  and  Stadeler^  in  the  urine  of 
dogs  which  had  breathed  chlorine,  and  in  the  urine  of  those 
animals  into  whose  lungs  oil  had  been  introduced.  According  to 
the  views  prevailing  at  that  time,  its  presence  was  supposed  to  be 
due  to  deficient  oxidation  of  uric  acid.  Meissner  ^  found  it  in  the 
urine  of  dogs  after  feeding  them  sodium  urate,  although  there  had 
been  no  allantoin  in  the  urine  previously. 

Poduschka^  and  Pohl*  did  not  find  increased  excretion  of 
allantoin  after  administration  of  uric  acid  to  dogs.  Poduschka 
performed  but  one  experiment.  He  did  find,  however,  that  from 
90  to  91  per  cent  of  the  allantoin  administered  to  dogs  is  excreted 
unchanged,  so  that  we  should  expect  to  find  increased  amounts  of 
this  body  in  the  urine  after  uric  acid  feeding,  if  any  is  formed  from 
uric  acid  in  the  body.  Luzzato '"  and  Minkowski  ®  likewise  found 
that  a  large  part  of  the  allantoin  fed  to  dogs  is  excreted  unchanged. 

Salkowski  ^  fed  8  grams  uric  acid  to  a  dog  in  two  days.  From 
the  urine  he  obtained  1.42  grams  allantoin  by  crystallization. 
This  is  about  18  per  cent  of  the  weight  of  uric  acid  given.  Swain  ^ 
found  that  from  10  to  20  per  cent  of  the  uric  acid  fed  to  dogs 
appears  as   allantoin  in  the  urine.     According  to   Salkowski's  ^ 


1  F.  Frerichs  und  G.  Stadeler.  Ueber  das  Vorkommen  von  Allantoin  im  Harn  bei 
gestorter  Respiration.     Miiller's  Arch,  fiir  Anat.  und  Physiol.,  393    (1854). 

2  G.  Meissner.  Beitrage  zur  Kenntniss  des  Stoffwechsels  im  thierischen  Organismus 
Zeitschr.  fur  rationelle  Med.,  31,  3  Reihe,  234  (1868). 

3  R.  Poduschka.  Quantitative  Versuche  iiber  Allantoinausscheidung.  Arch,  fiir  exp 
Path.  u.  Pharmak.,  44,  59  (1899). 

^  J.  Pohl.  Ueber  Allantoinausscheidung  bei  Intoxicationen.  Arch,  fur  exp.  Path,  u 
Pharmak.,  48,  367  (1902). 

•''  A.  Luzzato.  Ueber  das  Verhalten  des  Allantoins  im  Tierkorper.  Zeitschr.  fiir  physiol 
Chem.,  38,  5.37  (1903). 

"  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologic  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

^  E.  Salkowski.  Bildung  von  Allantoin  aus  Harnsaure  im  Tierkorper.  Ber.  der  Dtsch 
chem.  Gesell.,  9,  719  (1876). 

*  R.  E.  Swain.  The  Formation  of  oAlIantoin  from  Uric  Acid  in  the  Animal  Body.  Am 
Journ.  of  Physiol.,  6,  38  (1901). 

'  E.  Salkowski.  Ueber  das  Verhalten  in  das  Magen  eingefiihrten  Harnsaure  im  Organ 
ismus.     Zeitschr.  fiir  physiol.  Chem.,  35,  495  (1902). 


196      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

indirect  method  of  experiment,  a  considerable  part  of  the  uric 
acid  absorbed  is  excreted  as  allantoin. 

Mendel  and  Brown  ^  fed  6  and  4^  grams  uric  acid  respectively 
to  two  cats  and  obtained  .5  and  .3  gram  allantoin  in  the  urine, 
an  amount  corresponding  to  about  8  per  cent  of  the  uric  acid 
administered.  These  authors  likewise  found  increased  allantoin 
after  the  intravenous  injection  of  uric  acid  and  urates  in  cats 
and  dogs.^  Kanger^  found  allantoin  to  the  extent  of  a  small  per 
cent  of  the  uric  acid  fed  in  the  urine  of  cats. 

Those  substances  which  give  increased  excretion  of  uric  acid 
in  man  give  increased  excretion  of  allantoin  in  the  dog.  Uric 
acid  is  probably  formed  first  and  then  oxidized  to  allantoin. 
Thus,  Minkowski  *  reported  that  the  administration  of  thymus ' 
to  dogs  caused  the  appearance  in  the  urine  of  a  nitrogenous  body 
which  he  named  ''  urotinsaure."  He  identified  this  body  later  ^  as 
allantoin. 

Cohn "  likewise  found  allantoin  in  the  urine  of  dogs  to  which 
calves'  thymus  had  been  administered,  and  Salkowski  ^  after 
feeding  pancreas.  Minkowski  ^  found  that  nucleic  acid  also 
gives  allantoin  in  the  urine,  and  that  hypoxanthin  is  excreted 
to  the  extent  of  about  77  per  cent  as  allantoin;  9-methyladenin 
also  causes  a  slightly  increased  excretion  of  allantoin.  The  in- 
creased excretion  of  allantoin  noticed  by  Salkowski  ^  after  a  meat 
diet  is  probably  due  to  the  hypoxanthin  in  the  meat  extract. 

It  is  interesting  to  note  that  adenin  and  7-methyladenin,  which 
give  little  or  no  increased  excretion  of  uric  acid,  according  to  most 
authors,  when  administered  free  to  man,  give  no  allantoin  in  dogs. 

1  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the  Cat, 
especially  in  the  Excretion  of  Uric  Acid  and  Allantoin.  Am.  Journ.  of  Physiol.,  3,  261 
(1900). 

2  L.  Mendel  and  B.  White.  On  the  Intermediary  Metabolism  of  the  Purin  Bodies. 
The  Formation  of  Allantoin  in  the  Animal  Body.     Am.  Journ.  of  Physiol.,  12,  85  (1904). 

3  A.  Kanger.  Ueber  die  Moglichkeit  einer  Steigerung  der  Harnsaureausscheidung  bei 
Katzen  durch  Einfuhr  reiner  Harnsaure  per  os.     Pfliiger's  Archiv,  100,  428  (1903). 

*  O.  Minkowski.  Ueber  Stoffwechselprodukte  nach  Thymusfiitterung.  Verhandl.  des 
16t  Kongr.  fur  innere  Med.,  271  (1898). 

^  Ibid.  Ueber  Stoffwechselprodukte  nach  Thymusfiitterung.  Centralblatt  fiir  innere 
Medizin,  19,  500  (1898). 

6  T.  Cohn.  Beitrag  zur  Kenntniss  des  Stoffwechsels  nach  Thymusnahrung.  Zeitschr. 
fiir  physiol.  Chem.,  25,  507  (1898). 

''  E.  Salkowski.  Ueber  das  Vorkommen  von  Allantoin  im  Harn  nach  Fiitterung  mit 
Pancreas.     Centfalbl.  fur  med.  Wissensch.,  36,  929  (1898). 

^O-.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathol ogie  der  Harnsaure  bei 
Saugethieren.     Arch,  fur  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

^  E.  Salkowski.  Ueber  das  Vorkommen  von  Allantoin  und  Hippursaure  im  Hundeharn. 
Ber.  der  Dtsch.  chem.  Gesell.,  11,  500  (1878). 


Physiology  197 

Stadthagen^  found  that  guanin,  from  which  Uttle  or  no  uric  acid 
is  obtained,  when  it  is  administered  free  to  man,  gives  no  allantoin 
in  dogs. 

Mendel  and  Brown  ^  found  allantoin  in  the  urine  of  cats  after 
they  had  fed  on  thymus  and  pancreas,  and  Mendel,  Underhill, 
and  White  ^  found  allantoin  in  the  urine  of  dogs  and  cats  after 
the  administration  of  nucleic  acid  intravenously,  intraperitoneally, 
subcutaneously,  per  rectum,  and  by  the  mouth.  The  nucleic 
acid  was  obtained    from  wheat  embryo. 

Borrisow,'*  Poduschka,'  and  Pohl  '^  found  increased  amounts 
of  allantoin  in  the  urine  of  dogs  after  hydrazin  poisoning.  Ac- 
cording to  Borrisow,  the  autopsy  showed  that  the  liver  had  been 
acted  upon,  and  Poduschka  noted  a  degeneration  of  the  nuclei 
of  the  liver  cells  of  dogs  poisoned  with  hydrazin.  PohP  found 
that  there  is  no  allantoin  in  the  fresh  liver  or  spleen  of  starving 
dogs.  In  the  fresh  liver  and  spleen  of  dogs  which  had  been 
poisoned  with  hydrazin  he  found  allantoin.  He  found  also  that 
allantoin  is  formed  when  the  liver,  spleen,  thymus,  and  pancreas 
of  the  dog  undergo  autolysis.  He  did  not  find  allantoin  among 
the  products  of  autolysis  of  muscle  or  blood.  These  facts  taken 
together  seem  to  indicate  that  the  endogenous  uric  acid  from  the 
nucleoproteid  of  the  body  cells,  like  the  exogenous  uric  acid,  is 
oxidized  to  allantoin.  Thus  hydrazin,  by  causing  degeneration 
of  the  cell  nuclei  of  the  liver,  brings  about  increased  excretion  of 
allantoin  in  the  dog,  just  as  phosphorus  poison  or  sulphuric  acid 
injections,  by  causing  degeneration  of  the  liver  cells  in  man,  bring 
about  increased  excretion  of  uric  acid.  Hydroxylamin,  which 
Loewi  found  to  be  a  general  protoplasmic  poison  especially  active 
in  destroying  cells,  increases  the  excretion  of  allantoin  in  dogs, 
according  to  Pohl.'' 

1  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaure  in  verscheidenen  Organen,  ihre 
Verhalten  bei  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  Stickstoffbasen.  Vir- 
chow's  Archiv,  109,  390  (1887). 

2  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the  Cat, 
especially  on  the  Excretion  of  Uric  Acid  and  Allantoin.  Am.  Journ.  of  Physiol.,  3,  261 
(1900). 

3  L.  Mendel,  F.  Underhill,  and  B.  White.  Physiological  Studies  in  Nucleic  Acid.  Am. 
Journ.  of  Physiol.,  8,  377  (1903). 

4  P.  Borrisow.  Ueber  die  giftige  Wirkung  des  Diamids.  des  Dibenzoyldiamids  und 
iiber  das  Vorkommen  des  Allantoins  im  Harn.     Zeitschr.  fiir  physiol.  Chem.,  19,  499  (1894). 

5  R.  Poduschka.  Quantitative  Versuche  (iber  Allantoinausscheidung.  Arch,  fiir  e.xp. 
Path.  u.  Pharmak.,  44,  59  (1899). 

^  J.  Pohl.  Ueber  Allantoinausscheidung  bei  Intoxicationen.  Arch,  fiir  exp.  Path.  u. 
Pharmak.,  48,  367  (1902). 


198      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Oxidation  to  Oxalic  Acid 

It  is  difficult  to  decide  whether  or  not  any  oxalic  acid  is 
formed  by  the  oxidation  of  uric  acid  and  the  purin  bases  in  the 
dog.  In  the  first  place,  it  is  not  fully  settled  how  much  of  the 
oxalic  acid  formed  or  absorbed  by  the  system  is  excreted 
unchanged.  Wohler/  the  earliest  experimenter  on  this  subject, 
obtained  crystals  of  calcium  oxalate  in  urine  after  feeding  2 
drams  of  oxalic  acid  to  a  dog.  Gagiio  ^  found  oxalic  acid  in 
the  urine  of  dogs  after  administration  of  from  .0005  to  .001 
gram  of  oxalic  acid,  although  the  urine  had  previously  been  free 
from  it.  Pohl  ^  obtained  in  the  urine  practically  the  whole  of 
the  oxalic  acid  administered  after  feeding  11.2  and  11.8  milli- 
grams in  two  cases  to  a  dog.  Faust*  always  found  in  the  urine 
from  92  to  95  per  cent  of  the  oxalic  acid  fed  to  a  dog.  The  dose 
varied  from  .05  to  .5  gram. 

Auerbach,^  on  the  other  hand,  found  only  from  4^  to  5|  per 
cent  of  the  oxalic  acid  which  he  fed  to  dogs  in  the  urine.  Guinti,® 
too,  found  that  the  greater  part  of  the  oxalic  acid  eaten  by  dogs 
is  destroyed.  lOemperer  ^  found  that  sodium  oxalate  injected 
into  the  circulation  of  the  dog  is  partly  destroyed.  Calcium 
oxalate  is  not  destroyed.  According  to  Abeles,^  the  adminis- 
tration of  calcium  oxalate  per  os  to  dogs  does  not  increase  the 
excretion  of  oxalic  acid.  The  evidence  is  somewhat  conflicting, 
but  it  seems  most  probable  that  some,  at  any  rate,  of  the  oxalic 
acid  introduced  into  the  system  appears  in  the  urine.  Hence,  if 
oxalic  acid  were  formed  by  the  oxidation  of  uric  acid,  we  should 
expect  a  slight. increase  in  its  excretion  after  injection  of  purin 
bodies. 

1  Wohler.  Versuche  tiber  den  Ubergang  von  Materien  in  den  Harn.  Zeitschr.  fiir 
Physiol.,  1,  125  (1824). 

-  G.  Gagiio.  Ueber  die  Unveranderlichkeit  des  Kohlenoxydes  und  der  Oxalsaure  im 
thierischen  Organismus.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  22,  235  (1887). 

3  J.  Pohl.  Ueber  den  oxydativen  Abbau  der  Fettkbrper  im  tluerischen  Organismus. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  37,  413  (1896). 

■*  E.  Faust.  Ueber  die  Ursachen  der  Gewohnung  an  Morphin.  Arch,  fiir  exp.  Path, 
u.  Pharmak.,  44,  217  (1900). 

■''  A.  Auerbaeh.  Zur  Kenntniss  der  Oxydationsprocesse  im  Thierkorper.  Virchow's 
Archiv,  77,  226  (1879). 

8  L.  Guinti.  Die  Oxydirbarkeit  der  Oxalsaure  im  Organismus  der  Saugethiere  und 
Vogel.  Annali  di  chimica  e  di  farmacologie,  25,  10  (1897),  and  Maly's  Jahresb.  iiber  die 
Fortschritte  der  Thierchemie,  27,  SO  (1897). 

^  G.  Klemperer  und  F.  Tritschler.  Untersuchungen  iiber  Herkunft  imd  LosKehkeit 
der  im  Urin  ausgeschiedenen  Oxalsaure.     Zeitschr.  fiir  klin.  Medizin,  44,  337  (1902). 

8  M.  Abeles.  Ueber  alimentare  Oxalurie.  Wiener  klin.  Wochenschrift,  5,  227  and 
296  (1892). 


Physiology  199 

Wohler  and  Frerichs/  who  first  directed  attention  to  tliis 
point,  found  a  sediment  of  calcium  oxalate  in  the  urine  after 
injection  of  ammonium  urate  into  a  dog.  Gallois  ^  and  Zabelin  ^ 
could  not  confirm  the  results  of  Wohler  and  Frerichs.  Hammer- 
bacher  *  did  not  observe  an  increase  in  the  excretion  of  oxalic  acid 
after  feeding  uric  acid  to  dogs. 

Salkowski  ^  offered  as  evidence  against  the  theor}-  that  oxalic 
acid  can  come  from  uric  acid  in  the  dog  the  fact  that  dog's  liver, 
which  oxidizes  uric  acid,  contains  much  less  oxalic  acid  than 
calves'  liver,  which  does  not  oxidize  uric  acid.  From  the  fact 
that  there  is  no  relation  between  the  amount  of  uric  acid  and  the 
amount  of  oxalic  acid  in  the  dog's  urine,  Dunlop®  concluded 
that  uric  acid  is  not  oxidized  to  oxalic  acid.  Both  of  these  ob- 
jections are  invalid,  since  oxalic  acid  may  come  also  from  other 
sources  than  uric  acid. 

Swain  ^  and  Luzzato  *  found  a  slight  increase  in  the  excretion 
of  oxalic  acid  after  feeding  uric  acid  to  dogs.  This  is  what  we 
should  expect  if  allantoin  is  formed  from  uric  acid,  for  Luzzato  ^ 
has  shown  that  the  administration  of  allantoin  brings  about  a 
slight  increase  in  the  excretion  of  oxalic  acid  in  dogs. 

Oxidation  to  Parabanic  Acid,  Alloxan,  AUoxantin,  and  Glycocoll 

Parabanic  acid,  alloxan,  and  alloxantin  are  mostly  oxidized 
when  given  to  dogs,^°  so  that  it  is  not  easy  to  determine 
if  any  of  these  bodies  are  formed  by  the  oxidation  of  uric  acid. 

1  F.  Wohler  und  F.  Frerichs.  Ueber  Veranderungen,  welche  namentlich  organische 
Stoffe  beim  ihren  Uebergang  in  den  Ham  erfahren.  Annal.  d.  Chem.  u.  Pharm.,  65,  335 
(1848). 

2  Gallois.     Experiences  sur  I'ur^e  et  les  urates.     Comptes  rendus,  44,  734  (1857). 

3  Zabelin.  Ueber  die  Umwandling  der  Harnsaure  im  Thierkorper.  Annal.  d.  Chem. 
u.  Pharm.,  2  Suppl.,  326  (1863). 

*L.  Hammerbacher.     Zui  Physiologie  der  Oxalsaure.     Pfliiger's  Archiv,  33,  89  (1884). 

5  E.  Salkowski.  Ueber  Entstehung  und  Ausscheidung  der  Oxalsaure.  Berl.  klin. 
Wochenschrift,   37,   434   (1900). 

"  J.  Dunlop.  The  Excretion  of  Oxalic  Acid  in  Urine,  and  its  Bearing  on  the  Patho- 
logical Condition  Known  as  Oxaluria.  The  Journal  of  Pathology  and  Bacteriology,  3, 
389   (1894-5). 

■^  R.  Swain.  The  Formation  of  Allantoin  from  Uric  Acid  in  the  Animal  Body.  Am. 
Journ.  of  Physiol.,  6,  38  (1901). 

5  A.  Luzzato.  Ueber  das  Verhalten  des  Allantoins  im  Tierkorper.  Zeitschr.  fiir  physiol. 
Chem.,  38,  537  (1903). 

^  Ibid.  Zur  Physiologie  der  Oxalsiiure  im  Harn.  Zeitschr.  fiir  physiol.  Chem.,  37,  225 
(1903). 

'"  Koehne.  Ueber  das  Verhalten  einiger  Saureamide  im  tierischen  Organismus.  Inaug. 
Dissert.,  Rostock  (1894),  and  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  24, 
83  (1894). 


200      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

A  repetition,  on  dogs,  of  Wiener's  work  on  the  formation  of 
glycocoll  from  uric  acid  in  rabbits  would  not  be  of  any  value,  for 
Bunge  and  Schmiedeberg  ^  have  shown  that,  in  the  dog,  hippuric 
acid  is  synthesized  only  in  the  kidneys.  Further,  Schmiedeberg  ^ 
and  Minkowski  ^  have  shown  that  after  the  hippuric  acid  is  syn- 
thesized, it  is  again  partly  decomposed  into  benzoic  acid  and 
glycocoll  by  a  ferment. 

SUMM.\RY 

The  evidence,  then,  seems  in  favor  of  the  view  that,  in  the  dog, 
the  endogenous  and  exogenous  uric  acid  is  excreted  in  ver}^  small 
part  as  uric  acid.  The  greater  portion  seems  to  be  destroyed. 
A  part,  the  size  of  the  fraction  is  not  settled,  is  oxidized  to  allan- 
toin.  The  larger  part  of  the  allantoin  is  excreted  unchanged. 
A  small  part  is  further  oxidized  and  excreted  partly  as  oxalic  acid 
and  urea. 

IN  MAN 

Early  Work 

Half  a  century  ago  it  was  believed  that  uric  acid  is  normally 
oxidized  to  urea.  According  to  Liebig,^  uric  acid  is  oxidized 
to  urea  and  oxalic  acid  in  man.  Wohler  and  Frerichs  ^  ob- 
tained calcium  oxalate  sediment  and  increased  excretion  of 
urea  in  the  urine  of  men  to  whom  ammonium  urate  had  been 
fed.  Stokvis  ^  also  noticed  an  increased  excretion  of  urea  after 
eating  uric  acid.  Neubauer  ^  found  oxalate  sediment  in  the 
urine  when  uric  acid*  had  been  administered  the  night  before. 
He  believed  that  the  presence  of  the  oxalate  is  an  indication  of 
the  retardation  of  the  oxidation  processes  during  sleep,  that  in 

1  G.  Bunge  und  O.  Schmiedeberg.  Ueber  die  BUdung  der  Hippursaure.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  6,  233  (1876). 

^  O.  Schmiedeberg.  Ueber  die  Spaltungen  und  Synthesen  im  Tierkorper.  Arch,  fiir 
exp.  Path.  u.  Pharmak.,  14,  379  (1881). 

3  O.  Minkowski.  Ueber  Spaltungen  im  Thierkorper.  Arch,  fiir  exp.  Path.  u.  Pharmiak., 
17,  445  (1883). 

*  J.  Liebig.  Animal  Chemistry  or  Organic  Chemistry  in  its  Application  to  Physiology 
and  Pathology.     Transl.  by  W.  Gregory.     Ed.  by  W.  Webster  (1843). 

5  F.  Wohler  und  F.  Frerichs.  Ueber  Veranderungen,  welche  namentlich  organische 
Stoffe  bei  ihrem  Uebergang  in  den  Harn  erfahren.  Annal.  d.  Chem.  u.  Pharm.,  65,  335 
(1848). 

^  B.  Stokvis.  Bijdragen  tot  de  physiologic  van  het  acidum  uricum.  Ned.  Tijdschr., 
3,  587,  und  607  Afl.,  Oct.  (1859).  Arch.  f.  d.  holl.  Beitr.,  2,  260  (1860),  and  Schmidt's 
Jahresb.,  109,  4  (1861). 

'  C.  Neubauer.  Ueber  die  Zersetzung  der  Harnsaure  im  Thierkorper.  Annal.  d.  Chem. 
u.  Pharm.,  99,  206  (1856). 


Physiology  201 

the  daytime  the  oxalic  acid  would  be  oxidized  to  carbon  dioxide 
and  water.  Gallois  ^  noticed  in  one  case  a  sediment  of  calcium 
oxalate  after  administration  of  potassium  urate  to  a  man,  and 
Furbringer  ^  also  sometimes  found  an  increased  sediment  of 
oxalate  after  administration  of  ammonium  urates  to  man.  We 
know  now  that  the  presence  of  a  sediment  of  calcium  oxalate  in 
the  urine  does  not  necessarily  indicate  large  amounts  of  oxalate 
in  the  urine.  The  occurrence  of  an  oxalate  sediment,  like  the 
occurrence  of  a  urate  sediment,  depends  on  other  factors.  In 
the  method  of  determining  the  urea  used  by  these  early  authors, 
uric  acid,  creatin,  and  other  nitrogenous  bodies  were  also  deter- 
mined.    Their  conclusions,  therefore,  are  of  no  value. 

Excretion  as  Uric  Acid 

Until  very  recently,  it  has  been  believed  that  the  human 
organism  possessed  the  power  of  destroying  uric  acid  introduced 
from  without.  Garrod  ^  did  not  find  that  the  administration 
of  uric  acid  caused  an  increased  excretion  of  uric  acid.  Wein- 
traud  *  could  not  observe  an  increased  excretion  of  uric  acid 
after  feeding  4  to  6  grams,  or  Weiss  ^  after  feeding  10  grams  to 
men.  The  question  of  whether  or  not  the  acid  was  absorbed  was 
not  considered. 

According  to  Mitscherlich,"  on  the  other  hand,  uric  acid  is  not 
destroyed  by  the  organism.  Haig^  found  about  three  fourths  of 
the  uric  acid  which  he  ate  in  the  urine.  He  used,  however,  an 
inaccurate  method  for  the  determination  of  uric  acid,  and  his 
results  were  further  vitiated  by  the  fact  that  he  was  taking  also 
sodium  salicylate,  a  drug  which  increases  the  excretion  of  uric 
acid. 

According  to  Loewi,®  all  the  uric  acid  introduced  into  the  body 

'  Gallois.     Experiences  sur  I'urfe  et  les  urates.     Comptes  rendus,  44,  734  (1857). 

-  P.  Furbringer.  Zur  Oxalsaure  Ausscheidung  durch  den  Ham.  Deutsche  Arch,  fur 
klin.  Medizin,  18,  143  (1876). 

3H.  Garrod.  Uric  Acid:  Its  Physiology  and  its  Relation  to  Renal  Calcuh  and  Gravel. 
Brit.  Med.  Journ.,  1,  547  (1883). 

*  Weintraud.  Ueber  Harnsaure  im  Blute  und  ihre  Bedeutung  fur  die  Entstehung  der 
Gicht.     Wiener  klin.  Rundschau,  10,  3  (1896). 

s  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fur  physiol.  Chem.,  27,  217  (1899). 

8  Mitscherlich.  De  acidi  oxaUci,  etc.,  effectu  in  animalibus  observatis.  Inaug.  Dissert., 
Berl.  (1845). 

'  Haig.     On  Uric  Acid  as  a  Factor  in  Causation  of  Disease.     London  (1896). 

^O.  Loewi.  Beitrage  zur  Kenntniss  des  Nukleinstoffwechsels.  1.  Mitth.  Arch,  fiir 
exp.  Path.  u.  Pharmak.,  44,  1  (1901). 


202      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

is  excreted  unchanged.  To  three  men  who  were  living  on  a 
standard  diet,  he  fed  thymus.  The  increased  excretion  of  PjOg 
after  the  addition  of  thymus  to  the  diet,  according  to  Loewi,  is 
a  measure  of  the  amount  of  nucleins  absorbed  and  oxidized. 
Since,  in  all  three  cases,  he  found  that  the  ratio  of  the  increased 
excretion  of  PjOg  to  the  increased  excretion  of  uric  acid  is  the 
same,  he  concluded  that  all  the  uric  acid  formed  from  the  purin 
bases  of  the  thymus  is  excreted  unchanged,  for  otherwise  it  would 
be  necessary  to  assume  that  the  different  individuals  form  the 
same  amount  of  uric  acid  and  destroy  the  same  amount.  Further, 
according  to  Loewi,  if  we  use  Schindler's  ^  determinations  of  the 
amount  of  purin  bodies  in  thymus,  the  amount  of  uric  acid  in  the 
urine  after  thymus  feeding  will  correspond  quantitatively  to  the 
purin  bases  ingested. 

As  we  have  seen  in  an  earlier  part  of  this  work,  the  increased 
excretion  of  PjOj  after  thymus  feeding  is  not  a  measure  of  the 
amount  of  nuclein  absorbed  and  excreted.  Further,  Burian  and 
Schur  ^  have  shown  that  the  ratio  of  the  increased  excretion  of 
P2O5  to  the  increased  excretion  of  uric  acid  is  not  the  same  in 
different  individuals.  And,  finally,  the  best  determinations  of  the 
amount  of  purin  bases  in  thymus  show  that  Schindler's  figures 
are  far  too  low.^ 

Burian  and  Schur  *  injected  uric  acid  into  a  man  and  found 
that  about  50  per  cent  is  excreted  unchanged.  It  will  be  remem- 
bered that  they  found  about  50  per  cent  of  the  hypoxanthin 
given  in  the  food  is  excreted  as  uric  acid.  It  seems  probable, 
then,  that  practically  the  whole  of  the  hypoxanthin  must  be 
oxidized  to  uric  acid,  and  that  about  one  half  of  this  uric  acid  is 
oxidized  and  about  one  half  excreted  unchanged. 

Oxidation  to  Oxalic  Acid 

It  is  difficult  to  say  in  what  way  uric  acid  is  oxidized  in  the 
body  of  man.     In  regard  to  oxalic  acid,  it  is  not  fully  settled  just 

1  S.  Schindler.  Beitrage  zur  Kenntniss  des  Adenins,  Guanins,  und  ihrer  Derivate. 
Zeitschr.  fur  physiol.  Chem.,  13,  432  (1889). 

2  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Puriukorper  im  menschlichen 
Stoffweehsel.      1.  Mitth.     Pfliiger's  Archiv,  80,  241   (1900). 

3  Ibid.    Also 

R.  Burian  und  J.  Hall.  Die  Bestimmung  der  Purinstoffe  in  tierschen  Organen  mittels 
der  Methode  des  korrigierten  wertes.     Zeit.?chr.  fiir  physiol.  Chem.,  38,  336  (1903). 

■*  Pi.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Parinkorper  im  menschlichen  Stoff- 
wechsels.     2.  Mitth.     Pfliiger's  Archiv,  S7,  239  (1901). 


Physiology  203 

what  fraction  of  this  is  destroyed  when  it  is  introduced  into  the 
body. 

After  the  administration  of  oxalic  acid  and  oxalates,  calcium 
oxalate  was  found  in  the  urinary  sediment  by  Duckworth/  and  by 
Rabuteau.^  Buchheim  ^  fed  oxalic  acid  and  sodium  oxalate  to 
man  and  found  from  8  to  14  per  cent  unchanged  in  the  urine. 
According  to  Rotter/  small  amounts  of  oxalic  acid  are  excreted 
completely  unchanged.  According  to  Abeles/  small  amounts 
of  oxalic  acid  are  oxidized  completely  in  the  body.  Large  amounts 
bring  about  intestinal  disturbances  which  cause  oxaluria,  and 
this  explains  the  presence  of  oxalic  acid  in  the  urine  after  admin- 
istration of  large  amounts. 

Marfori/  Giunti/  Lom.mel/  and  Klemperer  and  Tritschler  ^ 
found  that  a  small  part  only  of  the  oxalic  acid  in  the  food  is  ex- 
creted unchanged.  Pierallini  ^'^  found  that  a  small  per  cent  of  the 
oxalic  acid  of  the  food  is  excreted  unchanged. 

Esbach^^  swallowed  5  grams  oxalic  acid  and  found  .181  gram 
or  3.6  per  cent  in  the  urine.  Dunlop  ^^  gave  .6  gram  oxalic  acid 
to  each  of  two  men  and  found  respectively  .024  and  .015  gram, 
or  4  per  cent  and  2.5  per  cent  in  the  two  urines.  In  another 
experiment, ^^  he  fed  .6  gram  oxalic  acid  to  a  man  and  found  3.6 

ID.  Duckworth.     Notes  on  Oxaluria.     St.  Barth.  Hosp.  Rec,  London,  2,  160  (1866). 

2  Rabuteau.  Contribution  h  I'^tude  du  mode  d'^limination  et  des  effets  toxiques  de 
I'acide  oxalique  et  des  oxalates.     Gazette  mM.  de  Paris,  4th  ser.,  3,  74  (1874). 

3  Buchheim.  Ueber  den  Uebergang  einiger  organischen  Sauren  in  den  Harn.  Arch, 
f.  physiol.  Heilk.,  Neue  Folge,  1,  122  (1857). 

*  Rotter.  Footnote  in  Wiener's  article,  Ueber  Zersetzung  und  Bildung  der  Harnsaure 
im  Thierkorper.     Arch,  fur  exp.  Path.  u.  Pharmak.,  42,  379  (1899). 

6  M.  Abeles.  Ueber  Alimentaire  Oxalurie.  Wien.  klin.  Wochenschrift,  5,  277  und  296 
(1892). 

8  P.  Marfori.  Sulle  tranzformazioni  di  alcuni  acidi  della  serie  ossalica  nell'  organismo 
deir  uomo.  Annali  de  chimica  e  di  farmacologica,  12,  250  (1890),  and  Maly's  Jahresb. 
uber  die  Fortschritte  der  Thierchemie,  20,  90  (1890). 

Ibid.  Ueber  das  Verhalten  der  Oxalsaure  im  Organismus.  Annali  di  chimica  e  di  farma- 
cologica, 25,  fasc.  5  (1897),  and  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  27, 
80  (1897), 

^  L.  Giunti.  Die  Oxydirbarkeit  der  Oxalsaure  im  Organismus  der  Saugetiere  und 
Vogel.  Annali  di  chimica  e  di  farmacologia,  25,  10  (1897),  and  Maly's  Jahresb.  iiber  die 
Fortschritte  der  Tliierchemie,  27,  80  (1897). 

8  F.  Lommel.  Ueber  die  Herkunft  der  Oxalsaure  im  Harn.  Deutsche  Arch,  fiir  klin. 
Medizin,  63,  599  (1899). 

°  G.  Klemperer  und  F.  Tritschler.  Untersuchungen  iiber  Herkunft  und  Loslichkeit 
der  im  Urin  ausgeschiedenen  Oxalsaure.     Zeitschr.  fiir  klin.  Medizin,  44,  337  Q902). 

1°  G.  Pierallini.     Ueber  alimentare  Oxalsaure.     Virchow's  Archiv.,  160,  173  (1900). 

1'  G.  Esbach.    L'oxalurie.     Bull.  g^n.  der  therap.  medicale  et  chirurgicale,  Paris,  (1883). 

12  J.  Dunlop.  The  Excretion  of  OxaUc  Acid  in  Urine,  and  Its  Bearing  on  the  Patho- 
logical Condition  known  as  Oxaluria.     Journ.  of  Path,  and  Bact.   3,   389  (1S94-5). 

'3  Ihid.  Reports  from  the  Laboratory  of  the  Royal  College  of  Physicians,  Edinburgh 
(1897). 


204      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

per  cent  of  it  in  the  urine.  About  3  per  cent  of  the  oxalic  acid 
administered  to  a  man  by  Stradomsky  ^  was  found  again  in  the 
urine.  It  seems  most  probable,  then,  that  about  3  or  4  per  cent 
of  the  oxalic  acid  administered  per  os  .is  excreted  unchanged  in 
the  urine.  A  larger  fraction  of  the  oxalic  acid  absorbed  into  the 
system  would  probably  be  excreted  unchanged,  for,  according 
to  Stradomsky,^  about  33  per  cent  of  the  oxalic  acid  which  he 
fed  to  a  man  was  found  again  in  the  feces,  and  Klemperer  and 
Tritschler  ^  found  that  when  oxalic  acid  is  injected  into  the  cir- 
culation a  considerable  part  of  it  is  excreted  unchanged.  It  seems 
very  likely  that  if  uric  acid  is  oxidized  to  oxalic  acid  in  the  body, 
the  administration  of  uric  acid  or  purin  bodies  would  occasion 
an  increased  excretion  of  oxalic  acid. 

There  is  no  direct  evidence  that  uric  acid  is  oxidized  to  oxalic 
acid  in  man.  Klemperer  and  Tritschler  ^  fed  uric  acid  to  a  man. 
but  did  not  find  that  the  excretion  of  oxalic  acid  was  increased. 
Garrod  ^  had  observed  that  a  blood  serum  rich  in  uric  acid  gave 
calcium  oxalate  crystals  on  putrefaction,  and  had  based  his  view 
that  uric  acid  is  oxidized  to  oxalic  acid  in  the  body  on  that  fact. 
Klemperer  and  Tritschler  -  made  a  similar  observation.  They 
found  that  when  uric  acid  is  mixed  with  fresh  blood,  the  uric 
acid  disappears  and  oxalic  acid  appears. 

Mills  *  and  Stradomsky  ^  noticed  that  the  largest  amount  of 
oxalic  acid  is  found  in  the  urine  after  a  meat  diet.  Bunge  ^ 
denied  that  this  is  so.  This  increased  amount  of  oxalic  acid 
has  been  attributed  to  the  purin  bases  in  the  meat  extract, 
especially  in  view  of  the  fact  that  Dunlop  "^  has  found  that  there 
is  no  oxalic  acid  in  the  urine  after  a  milk  diet,  and  that  Salkow- 
ski,^  Stradomsky,^  and  Lommel  ^  have  found  that  addition  of 

1  N.  Stradomsky.  Die  Bedingungen  der  Oxalsaurebildung  im  menschlichen  Organ- 
i  smus.     Virchow's  Archiv,   163,  404  (1901). 

2  G.  Klemperer  und  F.  Tritschler.  Untersuchungen  iiber  Ferkunft  und  LosKchkeit 
der  im  Urin  augeschiedenen  Oxalsaure.     Zeitschr.  fur  klin.  Medizin,  44,  337  (1902). 

3  A.  Garrod.  The  Nature  and  Treatment  of  Gout  and  Rheumatic  Gout.  London 
(1859). 

*  W.  Mills.  Ueber  die  Ausscheidung  der  Oxalsaure  durch  den  Harn.  Virchow's  Ar- 
chiv, 99,  305  (1885). 

^  G.  Bunge.     Lehrbuch  der  physiologische  Chemie. 

s  J.  Dunlop.  The  Excretion  of  OxaUc  Acid  in  Urine,  and  Its  Bearing  on  the  Patho- 
logical Condition  known  as  Oxaluria.     .Journ.  of  Path,   and  Baot.   3,  389   (1894-5). 

'  E.  Salkowski.  Ueber  Entstehung  und  Ausscheidung  der  Oxalsaure.  Berl.  khn. 
Wochenschrift,  37,  434  (1900). 

8  F.  Lommel.  Ueber  die  Herkunft  der  Oxalsaure  im  Harn.  Deutsche  Arch,  fiir  klin. 
Medizin,  63,  599  (1899). 


Physiology  205 

large  amounts  of  pure  proteid  to  the  diet  does  not  increase  the 
excretion  of  oxalic  acid.  The  increased  excretion  of  oxalic  acid 
after  meat  diet  may  be  due  to  something  other  than  the  purin 
bases,  however.  Klemperer  and  Tritschler  *  have  found  that 
creatinin,  and  Lommel,^  Mohr  and  Salomon,^  and  Stradomsky  * 
that  gelatin,  both  of  which  are  found  in  meat,  increases  the  ex- 
cretion of  oxalic  acid. 

According  to  Salkowski  ^  and  Lommel,^  the  addition  of  thymus 
to  the  food  causes  an  increased  excretion  of  oxalic  acid.  Stra- 
domsky* and  Liithje,**  on  the  other  hand,  fed  thymus,  and  Mohr 
and  Salomon  ^  fed  both  thymus  and  pancreas  to  men,  but  observed 
no  increased  excretion  of  oxalic  acid.  Even  if  thymus  does  cause 
an  increased  excretion  of  oxalic  acid,  it  is  not  necessarily  an  indi- 
cation that  the  oxalic  acid  comes  from  uric  acid.  Cippolina  ^ 
has  found  that  there  is  more  oxalic  acid  in  the  thymus  than  in 
the  other  organs.  Further,  gelatin  and  other  substances  mav 
be  the  source  of  the  oxalic  acid,  and  in  this  case  Kutscher  and 
Schenck  *  believe  that  oxaminic  acid,  which  they  obtained  in 
the  oxidation  of  gelatin  by  calcium  permanganate,  is  the  source 
of  the  oxalic  acid. 

Cippolina  ^  believes  that  the  human  liver  can  oxidize  uric  acid 
to  oxalic  acid.  He  found  more  oxalic  acid  in  human  liver  that 
had  been  allowed  to  undergo  autodigestion  after  addition  of  uric 
acid  than  in  liver  to  which  uric  acid  had  not  been  added. 

According  to  Wiener,**  his  work  on  the  synthesis  of  uric  acid 
from  certain  of  the  dibasic  aliphatic  acids  indicates  that  a  relation 
between  the  uric  acid  and  oxalic  acid  of  the  urine  might  be  ex- 

1  G.  Klemperer  und  F.  Tritschler.  Untersuchungen  iiber  Herkunft  unci  Loslichkeit 
der  im  Urin  ausgeschiedenen  Oxalsaure.     Zeitschr.  fiir  klin.  Medizin,  44,  337  (1902). 

2  F.  Lommel.  Ueber  die  Herkunft  der  Oxalsaure  im  Harn.  Deutsche  Arch,  fiir  klin. 
Medizin,  63,  599  (1899). 

3  L.  Mohr  und  II.  Salomon.  Untersuchungen  zur  Physiologie  und  Pathologie  der 
Oxalsaurebildung-  und  ausscheidung  beim  Menschen.  Deutsche  Arch,  fur  klin.  Medizin, 
70,  486  (1901). 

■»  N.  Stradomsky.  Die  Bedingungen  der  Oxalsaurebildung  im  menschhchen  Organ- 
ismus.     Virchow's  Arcbiv,  163,  404  (1901). 

■''  E.  Salkowski.  Ueber  die  Bestimmung  der  Oxalsaure  und  das  Vorkommen  von 
Oxalsaure  im  Harn.     Zeitschr.  fiir  physiol.  Chem.,  29,  436  (1900). 

8  H.  Liithje.  Zur  physiologischen  Bedeutung  der  Oxalsaure.  Zeitschr.  fiir  klin. 
Medizin,  35,  271   (1898). 

"Cippolina.  Ueber  die  Oxalsaure  im  Organismus.  Berl.  klin.  Wochenschrift,  38,  544 
(1901). 

8  F.  Kutscher  und  M.  Schenck.  Zur  Kenntnis  der  O.xalurie.  Zeitschr.  fiir  physiol. 
Chem.,  43,  337  (1904). 

^  H.  Wiener.  Ueber  synthetische  Bildung  der  Harnsaure  im  Thierkflrper.  Verhandl. 
des  19t  Kongr.  fiir  innere  Med.,  383  (1901),  and  Hofmeister's  Beitriige,  2,  42  (1902). 


206      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

pected,  and  it  is  not  necessary  to  assume  that  uric  acid  is  decom- 
posed to  oxalic  acid,  for  certain  of  these  acids  are  partly  synthe- 
sized to  uric  acid  and  partly  oxidized  to  oxalic  acid.  But,  as 
we  have  seen,  it  is  doubtful  if  any  uric  acid  is  formed  in  man  by 
synthesis.  Another  point  to  be  taken  into  consideration  is  the 
fact  that  the  oxalic  acid  found  in  the  urine  may  not  have  been 
excreted  as  'such.  According  to  Luzzato '  and  Salkowski,^  the 
oxalic  acid  of  the  urine  increases  on  standing,  and  may  be  formed 
from  other  bodies  found  in  the  urine. 

Oxidation  to  Allantoin  and  Glycocoll 

If  allantoin  were  formed  in  man  by  the  oxidation  of  uric  acid, 
we  should  expect  to  find  it  in  the  urine.  Only  Wohler  and 
Frerichs  ^  found  allantoin  completely  destroyed  in  man.  Loewi  * 
fed  allantoin  to  a  man  and  found  a  small  part  unchanged  in  the 
urine.  Minkowski  ®  found  in  the  urine  about  20  per  cent,  and 
Poduschka  ^  from  30  to  50  per  cent  of  the  allantoin  the}^  fed  to 
men. 

Minkowski  ^  and  Loewi  ^  fed  thymus  to  men,  but  did  not  find 
allantoin  in  the  urine.  Loewi  *  found  no  allantoin  in  the  urine 
after  feeding  nuclein  to  man. 

No  attempts  have  been  made  to  find  out  if  glycocoll  is  formed 
by  the  oxidation  of  uric  acid  in  man. 

Summary 

In  man,  then,  about  half  the  uric  acid  introduced  into  the  cir- 
culation is  oxidized.  It  is  not  known  what  compounds  are 
formed  by  the  oxidation  of  the  uric  acid. 

1  A.  Luzzato.  Zur  Physiologie  der  Oxalsaure  und  Oxalsaure  im  Harn.  Zeitschr.  fiir 
Physiol.  Chem.,  37,  225  (1903). 

2  E.  Salkowski.  Zur  Kenntnis  des  Hams  und  des  Stoffwechsels  der  Herbivoren.  Vor- 
kommen  von  Allantoin  Indikanbestimmung.     Zeitschr.  fiir  phyriol.  Chem.,  42,  213  (1904) . 

3  F.  Wohler  und  F.  Frerichs.  Ueber  Veranderungen,  welche  namentlieh  organische 
Stoffe  bei  ihrena  Ubergang  in  den  Harn  erfahren.  Annal.  d.  Chem.  u.  Pharmak.,  65,  335 
(1848). 

^  D.  Loewi.  Beitrage  zur  Kenntniss  des  Nukleinstoffwechsels.  1.  Mitth.  Arch,  fiir 
exp.  Path.  u.  Pharmak.,  44,  1  (1901). 

5  O.  Minkowski.  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugethieren.     Arch,  fiir  exp.  Path.  u.  Pharmak.,  41,  375  (1898). 

^  R.  Poduschka.  Quantitative  Versuche  iiber  Allantoinausscheidung.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  44,  59  (1899). 

'Loewi.  Beitrage  zum  Nukleinstoffwechsel.  Sitzungsber.  der  Gesell.  zur  Beforderung 
der  gesammten  Naturwissensch.,  Marburg,  120  (1899). 


Physiology  "  207 

The   Organ   of   Formation  of   Uric   Acid 

The  question  of  the  organ  in  which  uric  acid  is  formed  in  the 
body  has  caused  a  very  great  amount  of  controversy.  Different 
authors  have  believed  that  the  liver,  spleen,  kidneys,  cartilage 
of  the  joint,  the  cells  of  the  intestinal  tract,  and  the  muscles  form 
the  uric  acid.  Until  it  was  understood  that  in  birds  uric  acid  is 
formed  chiefly  by  synthesis,  and  in  mammals  chiefly  by  the  oxi- 
dation of  purin  bases,  many  authors  had  believed  that  theories 
based  on  the  work  of  Strahl  and  Lieberkiihn,  Zalesky,  Chrzonsz- 
czewsky,  Meissner,  Pawlinoff,  v.  Schroder,  Colasanti,  and  others 
on  the  formation  of  uric  acid  in  birds  and  snakes  could  be  applied 
in  mammals.  The  work  on  birds  has  been  discussed  in  another 
place,  and  as  we  now  know  that  the  metabolism  of  uric  acid  is 
different  in  birds  and  mammals,  it  will  not  be  necessary  to  con- 
sider it  at  this  point.  The  erroneous  ideas  concerning  the  source 
and  behavior  of  uric  acid  in  mammals  have  likewise  led  to  many 
wrong  views  concerning  the  organ  in  which  it  is  formed.  The 
mistake  of  applying  the  facts  observed  in  one  mammal  to  mammals 
in  general,  the  use  of  inaccurate  methods  of  analysis,  and  the 
misinterpretation  of  the  facts  which  have  been  discovered,  have 
caused  as  much  confusion  in  this  subject  as  in  the  study  of  the 
metabolism  of  uric  acid.  The  views  of  the  different  authors 
will  first  be  presented,  and  then  considered  from  the  standpoint 
of  our  present  knowledge  of  the  metabolism  of  uric  acid. 

THPJ    KIDNEYS 

Hoppe-Seyler  ^  believed  that  the  uric  acid  excreted  is  only 
that  part  which  is  formed  in  the  kidneys.  According  to  this 
author,  uric  acid  is  oxidized  in  the  body,  so  that  if  any  is  formed 
by  other  organs,  it  is  destroyed  before  reaching  the  kidneys. 
We  now  know  that  uric  acid  is  not  completely  destroyed  in  the 
body,  that  a  fraction  of  the  uric  acid  formed  in  other  parts  of  the 
body  can  reach  the  kidneys  unchanged. 

It  has  also  been  stated  that  the  blood  does  not  contain  uric  acid , 
and  that  therefore  the  uric  acid  in  the  urine  must  be  formed 
where  the  urine  is  formed,  —  in  the  kidneys.     Yet  Garrod  -  and 

1 F.   Hoppe-Seyler.     Physiologische   Chemie.     Berlin    (1881). 

2  A.  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheumatism,  and  Bright's  Disease.  Jledico-Chirurgical  Transactions,  31,  83 
(1848). 


208      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Abeles  ^  have  found  uric  acid  in  normal  human  blood  in  health. 
Weintraud  ^  found  uric  acid  in  normal  human  blood  after  a  meal 
containing  thymus,  and  Abeles^  likewise  found  it  in  a  number 
of  normal  human  organs,  v.  Jaksch^  and  Klemperer*  did  not 
find  any  uric  acid  in  the  blood  of  normal  individuals,  but  they, 
and  also  Garrod,  Kam,^  and  Magnus-Levy  ^  did  find  it  in  the  blood 
of  persons  suffering  from  certain  diseases.  The  blood  does 
contain  uric  acid  therefore,  though  perhaps  at  times  in  such  smadl 
quantities  as  to  be  difficult  to  detect. 

Strahl  and  Lieberkiihn  ^  stated  that  they  found  uric  acid  in 
the  blood  of  cats  whose  kidneys  had  been  extirpated.  They 
looked  upon  this  as  proof  that  uric  acid  is  not  formed  in  the 
mammal  kidney.  Burian  and  Schur  ^  have  failed  to  confirm 
Strahl  and  Lieberkiihn's  observation.  As  we  shall  see  later, 
we  should  not  expect  to  find  uric  acid  in  the  blood  of  cats  and 
dogs  even  after  kidney  extirpation,  so  that  this  work  has  no 
bearing  on  the  facts  in  man  in  either  case. 

Dickinson,^  Bartels,^"  Fleischer,"  and  Wagner^-  found  the  excre- 
tion of  uric  acid  decreased  in  nephritis.  This  was  looked  upon 
as  evidence  that  the  kidneys  produce  uric  acid,  and  that  there 
is   a   decreased   production   of   uric   acid   when   the   kidneys   are 

1  M.  Abeles.  Ueber  Harnsaure  im  Blute  und  einigen  Organen  und  Geweben.  Wiss. 
med.  Jahrb.,  83,  479  (1887),  and  Jahresb.  iiber  die  Leistung  und  Fortschritte  in  die  ges- 
ammte  Medicin,  1,  130  (1887). 

2  W.  Weintraud.  Ueber  Harnsaure  im  Blute  und  ihre  Bedeutung  fiir  die  Entstehung 
der  Gicht.     Wien  klin.  Rundschau,  16,  3  (1896). 

3  R.  V.  Jaksch.  Ueber  die  klinische  Bedeutung  des  Vorkommen  von  Harnsaure  und 
Xanthinbasen  im  Blute,  den  Exudaten  und  Transudaten.  Prager  Festschrift,  79  (1870), 
and  Zeitschr.  fiir  Heilkunde,  11,  41.5  (1891),  also  Ueber  Uricacidaemie.  Deutsche  med. 
Wochenschrift,  16,  741   (1890). 

^  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
schrift, 21,  655  (1895). 

5  B.  Kam.  Bijdragen  tot  de  kennis  der  urinezuuruitscheidung.  Diss.  Leiden  (1898). 
Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  28,  573  (1898). 

6  A.  Magnus-Levy.  Ueber  den  Stoffwechsel  bei  acuter  und  chronisoher  Leukamie. 
Virchow's  Archiv,  152,  107  (1898). 

'^  Strahl  und  Lieberkiihn.  Harnsaure  im  Blute  und  einige  neue  Bestantheile  des  Urins. 
Berlin  (1848).     Jahresber.  iiber  die  Fortschritte  in  der  gesammten  Medicin  (1848). 

s  Burian  und  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Stoffwechsel. 
2.  Mitth.     Pfliiger's  Archiv,  87,  239  (1901). 

^  W.  Dickinson.  Diseases  of  the  Kidneys  and  Urinary  Derangements.  London 
(1875). 

1"  Bartels.  Nierenkrankheiten.  Ziemssen's  Handbuch  der  spec.  Pathol,  und  Therapie, 
IX,  1  (1877). 

11  R.  Fleischer.  Klinische  und  pathologisch-chemische  Beitrage  zur  Lehre  von  den 
Nierenkrankheiten.     Deutsche  Arch,   fur  klin.   Medizin,   29,    129   (1881). 

12  E.  Wagner.  Der  Morbus  Brightii.  Ziemssen's  Handbuch  der  spec.  Pathol,  und 
Therapie.  IX,  1  (18S2),  3  AuP..,  p.  18. 


Physiology  209 

diseased.  Becquerel/  Gorup-Besanez,^  Frerichs,^  Stadthagen/ 
and  Van  Ackeren/^  on  the  other  hand,  found  the  excretion  of  uric 
acid  normal,  and  Vogel^  found  it  even  high,  so  that  decreased 
excretion  of  uric  acid  could  not  be  considered  a  constant  symp- 
tom of  nephritis,  even  before  the  more  accurate  work  of  recent 
times. 

In  1895,  Kriiger  and  Wulff  ^  published  their  method  for  the 
determination  of  the  purin  bodies  in  the  urine.  By  use  of 
this  method,  Kolisch  and  Dostal  *  found  that  the  excretion  of 
the  purin  bodies  as  a  whole  is  normal  in  nephritis.  The  excretion 
of  uric  acid  is  decreased  and  that  of  purin  bases  is  increased. 
According  to  these  authors,  uric  acid  is  formed  normally  in  the 
kidneys  from  the  nucleins.  A  small  part  only  of  the  nucleins 
become  excreted  as  purin  bases.  In  nephritis,  the  action  of  the 
kidney  is  impaired  so  that  less  uric  acid  is  formed.  A  greater 
part  of  the  nucleins  are  excreted  as  purin  bases.  Only  Fodor  ^ 
and  Baginsky  and  Sommerfeld  ^^  confirmed  Kolisch  and  found 
that  the  ratio  of  the  quantity  of  uric  acid  to  the  quantity  of  purin 
bases  in  the  urine  is  decreased  in  nephritis. 

Unfortunately,  Kolisch  and  Dostal,  Fodor,  and  Baginsky  and 
Sommerfeld  all  used  the  Kriiger- Wulff  method  for  the  deter- 
mination of  purin  bodies  in  the  urine.     As  we  have  already  seen, 

1  Becquerel.  Semiotique  des  urines  ou  traits  des  alterations  de  I'urine  dans  les  maladies 
suivi  d'un  traits  de  la  maladie  de  Bright.     Paris,  509  (1841). 

2  Gorup-Besanez.     Arch,  fiir  Physiol.  Heilk.,  8,  712  (1859). 

3  Frerichs.  Die  Bright'sche  Nierenkrankheit  und  deren  Behandlung.  Braunschweig 
(1851). 

*M.  Stadthagen.  Ueber  das  Vorkommen  von  Harnsaure  in  verscheidenen  thierischen 
Organen,  ihr  Verhalten  bei  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  Stickstoff- 
basen.     Virchow's  Archiv,   109,   390   (1887). 

=  F.  Van  Ackeren.  Ueber  Harnsaureausscheidung  bei  einigen  Krankheiten  in  be- 
sondere  bei  Morbus  Brightii.     Charity  Annalen,  17,  206  (1892). 

''  Vogel.  Krankheiten  der  harnbereitendes  Organ.  Virchow's  Handbuch  der  spec. 
Pathol,  und  Therapie,  IV,  2,  Erlangen  (1856-1865). 

*■  M.  Kriiger  und  C.  Wulff.  Ueber  eine  neue  Methode  zur  quantitativen  Bestimmung 
der  sogenannten  Xanthinkorper  im  Harne.  Zeitschr.  fur  physiol.  Chem.,  20,  176 
(1895). 

8  R.  Kolisch  und  H.  Dostal.  Das  Verhalten  der  AUoxurkorper  in  pathologischen 
Harnen.     Wien  klin.  Wochenschrift,  8,  413,  and  435  (1895). 

R.  Kolisch.  Ueber  Verhalten  der  AUoxurkorper  im  Harn  bei  Nephritis.  Wiener  med. 
Blatter,  19,  117  (1896). 

^  G.  Fodor.  Ueber  das  Verhalten  der  Harnsaure  bei  Nephritis.  Centralblatt  fur  innere 
Medizin,  16,  865  (1895). 

1°  A.  Baginsky  und  Sommerfeld.  Ueber  Ausscheidung  von  Xanthinkorper  bei  Ne- 
phritis. Verhandl.  der  Berlin,  physiologisch.  Gesell.,  1895.  Du  Bois  Arch,  fiir  Physiol., 
562  (1895). 

A.  Baginskj'.  Ueber  das  Vorkommen  von  Xanthin,  Guanin,  und  Hypoxanthin. 
Zeitschr.  fiir  physiol.  Chem.,  8,  395   (1SS4). 


210      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Weintraud/  Zulzer,^  Laquer,^  Huppert/  Safkowski/  and  Flatow 
and  Reitzenstein  ^  have  shown  that  this  method  is  very  unre- 
liable. The  presence  of  albumin  in  the  urine,  as  in  cases  of 
nephritis,  would  affect  the  results  so  as  to  show  apparently  high 
purin  bases. 

Ascoli,^  Rommel,^  Martin,''  Albu,^°  and  Magnus-Levy "  have 
found  the  excretion  of  purin  bodies  normal  in  nephritis.  Magnus- 
Levy,^^  Albu,^°  and  Ascoli  ^  found  the  amount  of  uric  acid  in  the 
urine  normal  in  nephritis,  and  Laquer  ^^  and  Martin  ^"  found  it  often 
normal.  Rommel  ^  and  Ziilzer  "  found  the  excretion  of  uric  acid 
normal  and  often  high  in  nephritis,  v.  Noorden,^^  Ziilzer,^*  and 
Martin  ^^  found  that  the  ratio  of  the  amount  of  uric  acid  to  the 
amount  of  purin  bases  is  normal  in  nephritic  urine.  Kam  ^^ 
found  the  uric  acid  sometimes  high,  sometimes  normal,  and  some- 
times low.      Schmoll  "  found  after  feeding  nuclein,  and  Kam/*' 

1  Weintraud.     Beitrage  zum  Stofifwechsel  der  Gicht.     Charite  Annalen,  215  (1895). 

2  G.  Zulzer.  Ueber  die  Alloxurkorperausscheidung  im  Har3e  bei  Nephritis.  Berl. 
klin.  Wochenschrift,  33,  72  (1896). 

3  B.  Laquer.  Ueber  die  Kriiger-Wulflsche  Methode  der  Alloxurkorperbestimmung. 
Centralblatt  fiir  innere  Medizin,  17,  1129  (1896). 

*  H.  Huppert.  Ueber  die  Bestimmung  der  Xanthinbasen  nach  Kriiger-Wulff.  Zeitschr. 
fur  physiol.  Chem.,  22,  556  (1897). 

5  E.  Salkowski.  Ueber  die  Kriiger-Wulffsche  Methode  zur  Bestimmung  der  Alloxur- 
korper  im  Harne.     Deutsche  med.  Wochenschrift,  23,  213  (1897). 

•^  R.  Flatow  und  A.  Reitzenstein.  Zur  Xanthinbasenbestimmung  im  Urin.  Deutsche 
med.  Wochenschrift,  32,  354  (1897). 

^  G.  Ascoli.     Sul  comportamento  dei  corpi  allossurici  nelle  nefriti.     Ciinica  med.,  1898. 
Maly's  Jahresb.  uber  die  Fortschritte  der  Thierchemie,  29,  722  (1899). 

8  O.  Rommel.  Die  Ausscheidung  der  Alloxurkorper  bei  Gicht  und  Schrumpfniere. 
Zeitschr.  fur  kUn.  Medizin,  30,  200  (1896). 

9  C.  Martin.  Ueber  das  Ausscheidungsverhaltnisse  der  Alloxurkorper  bei  Nephritis. 
Centralblatt  fiir  innere  Medizin,  20,  625  (1899) ;  and  Maly's  Jahresb.  iiber  die  Fortschritte 
der  Thierchemie,  29  (1899). 

1"  Albu.  Discussion  of  Laquer's  Article:  Ueber  die  Ausscheidungsverhaltnisse  der  Allo- 
xurkorper im  Harne  von  Gesunden  und  Kranken.  Verhandl.  des  14t  Kongr.  fiir  innere 
Med.,  423  (1896). 

11  A.  Magnus-Levy.  Discussion  of  Laquer's  Article:  Ueber  die  Ausscheidungsverhalt- 
nisse der  Alloxurkorper  im  Harne  von  Gesunden  und  Kranken.  Verhandl.  des  14t  Kongr. 
fiir  innere  Med.,  423  (1896). 

1-  B.  Laquer.  Ueber  die  Ausscheidungverhaltnisse  der  Alloxurkorper  im  Harne  von 
Gesunden  und  Kranken.     Verhandl.  des  14t  Kongr.  fur  innere  Med.,  333  (1896). 

13  C.  Martin.  Ueber  die  Ausscheidungsverhaltnisse  die  Alloxurkorper  bei  Nephritis. 
Centralblatt  fiir  innere  Medizin,  20,  625  (1899). 

14  G.  Zulzer.  Ueber  die  Alloxurkorperausscheidung  im  Harn  bei  Nephritis.  Berl.  klin. 
Wochenschrift,  33,  72  (1896). 

15  v.  Noorden.  Discussion  of  Laquer's  Article:  Ueber  die  Ausscheidungsverhaltnisse 
der  Alloxurkorper  im  Harne  von  Gesunden  und  Kranken.  "^^erhandl.  des  14t  Kongr 
fur  innere  Med.,  420  (1896). 

16  B.  Kam.  Bijdragen  tot  de  kennis  der  urinezuuruitscheidung.  Diss.  Leiden  (1898). 
Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  28,  573  (1898). 

1^  E.  Schmoll.  Stoffweohselversuch  an  einem  Gichtkranken.  Zeitschr.  fiir  klin.  MeJi  - 
zin,  29,  510  (1896). 


Physiology  211 

and  Zagari  and  Pace  *  after  thymus  feeding,  that  there  is  in- 
creased excretion  of  uric  acid  just  as  in  health.  There  seems 
no  reason,  then,  to  assume  that  in  nephritis  we  have  abnormal 
quantities  of  uric  acid  or  purin  bodies  in  the  urine.  Malfatti  2 
could  not  obtain  uric  acid  from  purin  bases  by  passing  blood 
containing  purin  bases  through  an  isolated  kidney,  or  by  allowing 
the  kidney  of  a  calf  to  act  upon  the  purin  bases  in  spleen 
extract. 

There  is,  therefore,  no  indication  that  uric  acid  is  formed  in 
the  kidneys. 

THE    SPLEEN 

Scherer,^  Cloetta,'*  and  Gorup-Besanez  ''  found  uric  acid  in  ox 
spleen,  and  Scherer "  found  it  in  the  spleen  of  a  man  who  had 
leukemia.  Virchow^  observed  increased  uric  acid  sediment  in 
the  urine  and  uric  acid  concretions  in  cases  of  leukemia,  and 
Ranke^  found  the  excretion  of  uric  acid  increased.  These  f-acts 
led  Virchow  ^  to  believe  that  the  uric  acid  might  come  from  the 
spleen,  and  led  Ranke*  to  state  that  uric  acid  is  formed  in  the 
spleen. 

Only  Abeles  ^  has  since  found  uric  acid  in  the  fresh  human  spleen, 
and  Stokvis^^'in  the  spleen  of  a   calf.     Salomon,"  Salkowski,^^ 

1  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  al'  indirizzo  terapeutioo.     Centralblatt  fiir  innere  Medizin,  19,  816  (1898). 

2  H.  Malfatti.  Ueber  die  Alloxurkorper  und  ihr  Verhaltnisse  zur  Gicht.  Wien  klin. 
Wochenschrift,  9,  723  (1896). 

3  Scherer.  Ueber  einen  im  thierischen  Organismus  vorkommenden  dem  Xanthin- 
oxydverwandten  Korper.     Ann.  der  Chem.  u.  Pharm.,  73,  328  (18.50). 

*  A.  Cloetta.  Ueber  das  Vorkommen  von  Inosit,  Harnsaure,  etc.,  im  thierschen  Korper. , 
Ann.  der  Chem.  u.  Pharm.,  99,  289  (1856). 

5  E.  V.  Gorup-Besanez.  Ueber  die  chemischen  Bestandtheile  einiger  Driisensafte. 
Ann.  der  Chem.  u.  Pharm.,  98,  1  (1856). 

6  Scherer.  Untersuchungen  tiber  das  Blut  bei  Leukamie.  Verhandl.  d.  physik.  Mediz. 
Gesellsch.  zu  Wurzburg,  2,  321  (1851). 

Ihid.  Beitrag  zur  Geschichte  der  Leukamie.  Chemische  Untersuchungen  des  Blutes. 
Verhandl.  d.  physik.  Mediz.  Gesellsch.  zu  Wurzburg,  7,  123  (1856). 

''  R.  Virchow.  Zur  pathologischen  Physiologie  des  Blutes.  Virchow's  Archiv,  5,  43 
(1853). 

*  H.  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidung  der  Harnsaure  beim 
Menschen  (1858). 

'  M.  Abeles.  Ueber  Harnsaure  im  Blute  und  einigen  Organen  und  Gewebe.  Wien 
med.  Jahrb.,  83,  479  (1887),  and  Jahresb.  iiber  die  Fortschritte  der  gesammten  Medicin, 
1,   130   (1887). 

'"  B.  Stokvis.  Bijdragen  tot  de  physiologie  van  het  acidum  uricum.  Ned.  Tijdschr., 
3,  p.  587,  Afl.,  Oct.,  1859,  Arch.  f.  d.  holl..  Beitr.,  p.  260  (1860);  Schmidt's  Jahrk,  109. 
4  (1861). 

"  Salomon.     Arch.  f.  Physiol.,  762  (1876). 

'2  E.  Salkowski.  Chemische  untersuchungen  von  Leber  und  Milz  in  einen  Fall  von 
lienaler  Leukamie.     Virchow's  Archiv,  81,  166  (1880). 


212      The  Chemistry,  Physiology  and  Pathology  of  Uric  Acid 

and  Bockendahl  and  Landwehr  ^  found  no  uric  acid  in  leukemic 
spleen. 

An  absolute  increased  excretion  of  uric  acid  in  leukemia  has  been 
found  also  by  Berell,^  Bohland  and  Schurz,^  Hoffmann/  Fleischer 
and  Penzoldt,^  Sticker,**  Ebstein/  Magnus-Levy,*  Zagari  and  Pace,^ 
and  in  one  case  by  Galdi.^"  An  increase  in  the  ratio,  uric  acid  :  urea, 
has  been  found  by  Parkes,"  Jacubasch,^^  Hoffmann/  Reichardt/^ 
and  Schmuziger."  An  increased  excretion  of  purin  bases  was 
found  in  leukemia  by  Bondzynski  and  Gottlieb, ^^  and  by  Kolisch 
and  Dostal.^**  Bondzynski  and  Gottlieb  and  Kolisch  and  Dostal  ^*' 
used  the  Kriiger-Wulff  method  of  determination. 

The  work  of  Giacosa  "  and  Horbaczewski,^*  who  found  that  uric 
acid  is  formed  by  the  autolysis  of  ox  spleen,  and  the  work  of 

1  A.  Bockendahl  und  H.  Landwehr.  Chemisohe  Untersuchungen  leukamischen  Or- 
ganen.     Virchow's  Archiv,  84,  561. 

2C.  Berell.  Zur  Kasiiistik  der  Leukamie.  Medical  Times  and  Gazette,  284  (1868); 
Schmidt's  Jahrbuch,  142,  167  (1869). 

3  E.  Bohland  und  H.  Schurz.  Ueber  die  Harnsaure-  und  Stickstoffausscheidung  bei 
Leukamie.     Pfluger's  Archiv,  47,  469  (1890). 

*  K.  Hoffmann.  Harnbeschaffenheit  bei  Leukamie  lienalis.  Wien.  med.  Wochen- 
schrift,  20,  1036  (1870). 

5  R.  Fleischer  und  F.  Penzoldt.  Klinische,  pathologische,  anatomische,  und  chemische 
Beitrage  zur  Lehre  von  der  lienalen-,  myologenen-,  sowie  der  lymphatischen  Form  der 
Leukamie.     Deutsche  Arch,  fiir  klin.  Medizin,  26,  368  (1880). 

6  G.  Sticker.  Beitrage  zur  Pathologie  und  Therapie  der  Leukamie.  Zeitschr.  fiir 
klin.  Medizin,  14,  80  (1888). 

'  Ebstein.     Ueber  die  acute  Leuk.amie,  u.  s.  w.     Archiv.  fur  klin.  Med.,  44,  343. 

s  Magnus-Levy.  Ueber  den  Stoffwechsel  bei  acuter  und  chronischer  Leukamie.  Vir- 
chow's Archiv,  152,  107  (1898). 

8  G.  Zagari  e  D.  Pace.  La  genesi  dell'  aeido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  all'  indirizzo  terapeutico.  Napoli  (1897).  Centralblatt  fiir  innere  Medizin,  19, 
816  (1898). 

'"  F.  Galdi.  Ueber  die  Alloxurkorper  im  Stoffwechsel  bei  Leukamie.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  49,  213  (1903). 

'1  Parkes.     The  Composition  of  Urine.     London,  331  (1860). 

12  H.  Jacubasch.  Beitrage  zur  Harnanalyse  bei  lienaler  Leukamie.  Virchow's  Archiv, 
43,  196  (1868). 

13  E.  Reichardt.  Blut  und  Harn  bei  Leukamie.  Jenaische  Zeitung  f.  Medizin  und 
Naturwissenschaften,  5,  389  (1870). 

1^  F.  Schmuziger.  Beitrage  zur  Kenntniss  der  Leukamie.  Arch.  d.  Heilkunde,  17, 
273  (1876). 

15  Bondzynski  und  Gottlieb.  Ueber  Xanthinkorper  im  Harn  des  Leukamikers.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  36,  127  (1895). 

18  R.  Kolisch  und  H.  Dostal.  Das  Verhalten  der  Alloxurkorper  in  pathologischen 
Harnen.     Wien  klin.  Wochenschrift,  8,  413,   und  435   (1895). 

1'  P.  Giacosa.  Ueber  die  Bildung  der  Harnsaure  im  Organismus.  Acadamie  der  Medicin. 
Turin,  1890,  6  Juni.     Maly's  Jahresb.  uber  die  Fortschritte  der  Thierchemie,  21,  182  (1891). 

18  J.  Horbaczewski.  Untersuchungen  iiber  die  Entstehung  der  Harnsaure  im  Sauge- 
thierorganismus.     Monatshefte  fiir  Chemie,  10,  624  (1889). 

Ibid.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xanthinbasen 
sowie  der  Entstehung  der  Leukocytose  im  Saugethierorganismus.  Monatshefte  fur 
Chemie,  12,  221  (1891). 


Physiology  213 

Spitzer  ^  and  Wiener  -  who  confirmed  the  discovery  of  Giacosa 
and  Horbaczewski,  and  who  found  also  that  the  process  is  a  vital 
one  which  ceases  with  the  death  of  the  cells  of  the  spleen,  and  of 
Schittenhelm,^  who  prepared  the  active  enzyme,  has  already 
been  spoken  of. 

The  apparent  relation  between  the  spleen  and  the  formation 
of  uric  acid  has  led  many  authors  to  believe  that  uric  acid  is 
formed  in  the  spleen.  Neumeister  *  and  Hammarsten  ^  do  not 
say  precisely  in  their  textbooks  that  the  spleen  does  form  uric 
acid,  but  that  there  is  a  very  close  relationship  between  the  spleen 
and  the  formation  of  uric  acid. 

Other  authors  have  maintained  that  the  relation  between  the 
spleen  and  the  formation  of  uric  acid  is  not  so  very  close.  Thus, 
Mosler  and  Korner  ^  found  an  increased  excretion  of  uric  acid 
in  leukemia  only  when  fever  was  present.  Bartels  ^  noted  that 
splenic  tumors  sometimes  occur  without  giving  rise  to  an  in- 
creased excretion  of  uric  acid.  According  to  Stadthagen,®  cer- 
tain pathological  enlargements  of  the  spleen,  for  example,  pseudo- 
leukemia, occur  without  any  increased  excretion  of  uric  acid. 
In  the  case  of  a  patient  who  had  a  steadily  growing  tumor  of  the 
spleen,  Sticker^  found  that  the  quantity  of  uric  acid  in  the 
urine  varied  without  any  relation  to  the  growth  of  the  tumor. 
Matthes  ^"  found  the  excretion  of   uric  acid  normal  in  leukemia, 

1  W.  Spitzer.  Die  Uberfuhrung  von  Nukleinbasen  in  Harnsaure  durch  die  Sauerstoff- 
iibertragende  Wirkung  von   Gewebsausziigen.     Pfliiger's   Archiv,   76,    192   (1899). 

2  jj.  Wiener.  Ueber  Zersetzung  und  Neubildung  der  Harnsaure  im  thierischen  Korper. 
Verhandl.  des  17t  Kongr.  fur  innere  Med.,  622  (1899) ;    also 

Ihid.  Ueber  Zersetzung  und  Bildung  der  Harnsaure  im  Tierkorper.  Arch,  fiir  exp.  Path, 
u.  Pharmak.,  42,  375  (1900). 

3  A.  Schittenhelm.  Ueber  die  HarnsaurebUdung  im  Gewebsausziigen.  Zeitschr.  fiir 
physiol.  Chem.,  42,  251  (1904),    and 

Ihid.  Ueber  die  Fermente  des  Nukleinstoffwechsels.  Zeitschr.  fiir  physiol.  Chem., 
43,  228  (1904). 

*  Neumeister.     Lehrbuch  der  physiologischen  Chem.,  512  (1897). 

5  Hammarsten.     Text    Book   of   Physiological   Chemistry    (1898). 

^  F.  Mosler  und  W.  Korner.  Zur  Blut  und  Harnanalyse  bei  Leukamie.  Virchow's 
Archiv,  25,  142  (1862). 

F.  Mosler.  Zur  Diagnose  der  lienalen  Leukamie  und  der  chemischen  Beschafifenheit 
der  Transudate  und  Sekrete.     Virchow's  Archiv,  37,  43  (1866). 

^  Bartels.  Untersuchungen  iiber  die  Ursache  einer  gestiegerten  Harnsaureausscheidung 
in  Krankheiten.     Deutsch.  Arch,  fiir  klin.  Medizin,  1,  13  (1865). 

^  M.  Stadthagen.  Ueber  das  Vorkommen  von  Harnsaure  in  verschiedenen  thierischen 
Organen,  ihr  Verhalten  bei  Leukamie  und  die  Frage  ihrer  Entstehung  aus  den  Stickstoff- 
basen.     Virchow's  ArcMv,  109,  390  (1887). 

'  G.  Sticker.  Beitrage  zur  Pathologie  und  Therapie  der  Leukamie.  Zeitschr.  fiir  klin. 
Medizin,  14,  SO  (1888). 

I'' M.  Matthes.  Zur  Chemie  des  leukamischen  Blutes.  Berl.  klin.  Wochenschrift,  31, 
531    (1894). 


214      The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

and  Stuve/  Gumprecht,^  and  Magnus-Levy^  found  that  only  the 
normal  amount  of  uric  acid  is  excreted  in  chronic  leukemia. 
Increased  excretion  of  uric  acid  is  not,  therefore,  a  constant  symp- 
tom of  leukemia. 

Mendel  and  Jackson  *  found  that  splenectomy  does  not  affect 
the  excretion  of  uric  acid  in  dogs  and  cats  when  nuclein  is  ad- 
ministered or  when  it  is  not.  Lo  Monaco  ^  observed  no  decrease 
in  the  excretion  of  uric  acid  in  the  case  of  a  woman  whose  spleen 
had  been  extirpated.  The  evidence,  then,  does  not  indicate 
definitely  that  uric  acid  is  formed  in  the  spleen.  At  any  rate, 
the  spleen  is  not  the  only  organ  in  which  uric  acid  is  formed. 

CARTILAGE,   CELLS    OF    THE    DIGESTIVE    TRACT,    DIGESTIVE 
GLANDS,    AND    MUSCLES 

It  may  be  mentioned  that  Bartels "  believed  that  uric  acid  is 
formed  in  the  cartilage  of  the  joints.  According  to  this  author 
the  blood  supply  is  poor  in  the  joints  and  correspondingly  the 
oxidation  processes  defective.  Therefore,  uric  acid  is  formed. 
This  idea  is,  of  course,  based  on  the  old  view  that  uric  acid  is  a 
product  of  incomplete  oxidation  of  proteid. 

The  work  of  Mares,^  later  confirmed  by  Kam,^  who  found  the 
quantity  of  uric  acid  in  the  urine  at  different  periods  of  the  day 
parallel  with  the  activity  of  the  digestive  glands  is  worthy  of 
mention.  Mares  concluded  that  the  uric  acid  is  formed  by  the 
activity  of  the  cells  of  the  digestive  glands  from  the  material 
forming  the  cells. 

The  discovery  of  purin  bodies  in  the  feces  during  starvation  by 

1  R.  Stuve.  Beobachtungen  iiber  einem  Fall  von  lymphatischen  Leukamie.  Festschr. 
des  stadt  Krankenhauses  zu  Frankfurt  a.  M.  (1896). 

2  Gumprecht.  AUoxurkorper  und  Leukocyten  beim  Leukamiker.  Centralbl.  fiir 
allgem.  Path,  und  pathol.  Anat.,  7,  820  (1896). 

3  A.  Magnus-Levy.  Ueber  den  Stoffwechsel  bei  acuter  und  chronischer  Leukamie. 
Virchow's  Archiv,  152,  107  (1898). 

^  L.  Mendel  and  H.  Jackson.  On  Uric  Acid  Formation  after  Splenectomy.  Am.  Journ. 
of  Physiol.,  4,  163  (1900). 

5  D.  Lo  Monaco.  Osservazioni  sull'  escrezione  e  sulla  formazione  dell'  acido  urico 
nelP  organismo.  BoUetino  della  societa  Lancisiani  degli  ospedali  di  Roma.  14.  (2), 
102  (1894),  and  Schmidt's  Jahrbuch.,  252,  109  (1896). 

6  Bartels.  Untersuchungen  iiber  die  Ursache  einer  gesteigerten  Harnsaureausschei 
dung  in  Krankheiten.     Deutsche  Arch,  fiir  klin.  Medizin,  1,  13  (1865). 

^  F.  Mares.  Sur  I'origine  de  I'acide  urique  chez  I'homme.  Archives  slaves  de  Biologic, 
3  207  (1888);  Centralbl.  fur  die  med.  Wissen.,  25,  2  (1898);  Maly's  Jahresb.  iiber  die 
Fortscritte  der  Thierchemie,  18,  112  (1888). 

*  B.  Kam^.  Bijdragen  tot  de  kennis  der  urinezuuruitscheidung.  Dissert.  Leiden  (1898). 
Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  28,  573  (1898). 


Physiology  215 

Weintraud  ^  led  him,  and  later  Brandeburg  -  who  confirmed 
Weintraud's  discovery,  to  believe  that  at  least  a  j^art  of  the  uric 
acid  excreted  is  formed  by  or  from  the  mucous  membrane  of 
the  alimentary  canal.  The  discovery  of  purin  bodies  in  the 
feces  during  starvation,  in  which  case  they  cannot  come  from 
the  food,  has  been  confirmed  by  Petren,^  Kriiger  and  Schitten- 
helm,^  and  Galdi.^  Petren "  has  likewise  found  purin  bodies  in 
feces  free  from  bile.  This  work,  however,  does  not  give  us  any 
definite  indication  that  uric  acid  is  formed  by  any  of  the  cells  of 
the  digestive  tract. 

The  view  first  expressed  by  Siven^  that  uric  acid  is  formed  by 
muscular  activity  will  also  be  remembered.  His  view  is  based 
only  on  his  discovery  that  the  excretion  of  uric  acid  is  slightly 
increased  by  muscular  work.  In  view  of  the  work  of  Burian,^ 
we  'must  believe  that  muscular  activity  may  be  an  important 
source  of  the  endogenous  uric  acid. 

THE   LIVER 
According  to  Cloetta,^  Stokvis,^"  and  Abeles,^^  uric  acid  is  found 
in  the  liver  of  men,  swine,  the  ox,  and  the  horse.     These  authors, 

I  W.  Weintraud.  Zur  Entstehu'ng  der  Harnsaure  im  Saugethierorganismus.  Verhandl. 
des  14t  Kongr.  fiir  innere  Med.  (1896),  190,  Wiesbaden,  and  Wien  klin.  Rundschau,  2 
(1896);  also 

Ihid.     Beitrage  zum  Stoffwechsel  der  Gicht.     Charite  Annalen,  275  (1895),  also 

Ibid.  Ueber  Harnsaurebildung  beim  Mensehen.  Vortrag  geh.  in  der  physiol.  Gesell. 
zu  Berlin  am  Marz  (1895),  and  Du  Bois  Arch.,  382  (1895). 

-  C.  Brandeburg.  Ueber  die  diagnostische  Bedeutung  der  Harnsaure  und  Xanthin- 
basen  in  Urin.     Berl.  klin.  Wochenschrift,  33,  137  (1896). 

3  K.  Petren.  Ueber  das  Vorkommen,  die  Menge,  und  die  Abstanamung  der  Xanthin- 
basen  in  den  Faces.     Skandinav.  Arch.  f.  Physiol.,  8,  315  (1898). 

■*  M.  Kriiger  und  A.  Schittenhelm.  Die  Purinkorper  der  menschlichen  Faeces.  Zeitschr. 
fur  physiol.  Chem.,  35,   153   (1902). 

5  F.  Galdi.  Ueber  die  Alloxurkorper  im  Stoffwechsel  bei  Leukamie.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  49,  213  (1903). 

6  K.  Petren.  Nachtrag  zur  Mittheilung  iiber  das  Vorkommen  der  Xanthinbasen  in 
den  Faces.     Skandinav.  Arch.  f.  Physiol.,  9,  412  (1899). 

'  V.  Siven.  Zur  Kenntnis  der  Harnsaurebildung  im  menschlichen  Organismus  unter 
physiologischen  und  pathologischen  Verhaltnissen.  Skandinav.  Arch.  f.  Physiol.,  11,  123 
(1901). 

*  R.  Burian.  Die  Bildung  der  Harnsaure  im  Organismus  des  Mensehen.  Med.  Khn., 
1,  131  (1905),  and 

Ihid.  Die  Herkunft  der  endogenen  Harnpurin  bei  Mensch  und  Saugethiere.  Zeitschr. 
fur  physiol.  Chem.,  43,  532  (1905). 

"  A.  Cloetta.  Ueber  das  Vorkommen  von  Inosit,  Harnsaure,  etc.,  im  thierischen  Korper. 
Ann.  der  Chem.  u.  Pharm.,  99,  289  (1856). 

1°  B.  Stokvis.  Bijdragen  tot  de  physiologie  van  het  acidum  upcum.  Ned.  Tijdschr. 
IV,  p.  587,  Afi.,  Oct.,  1859.  Arch.  f.  d.  holl.  Beitr.,  p.  260  (1860),  und  Schmidt's  Jahrb., 
109,  4  (1S61). 

II  M.  Abeles.  Ueber  Harnsaure  im  Blute  und  einigen  Organen  und  Geweben.  Wien. 
med.  Jahrb.,  83,  479  (1887),  and  .Jahre.sb.  iiber  die  Fort.^chritte  der  ges.  Mc'l.,  1,  1.30  (1.SS7). 


216      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

however,  found  uric  acid  in  several  other  organs.  The  discovery 
cannot  be  considered  to  indicate  that  uric  acid  is  formed  in  the 
liver. 

Salomon  ^  and  Horbaczewski  ^  have  found  that  uric  acid  is 
formed  by  the  autodigestion  of  ox  liver  after  slight  decomposi- 
tion. Salkowski,^  Spitzer,*  and  Wiener  ^  found  that  this  is  a 
vital  process  which  ceases  when  the  cells  are  killed.  These  authors 
found  also  that  other  organs,  for  example,  spleen,  thymus,  pan- 
creas, give  uric  acid  in  the  same  way.  Wiener  found  further  that 
the  liver  can  oxidize  hypoxanthin  to  uric  acid.  The  liver  of  the 
dog  does  not  act  like  the  horse,  ox,  and  swine  liver  in  this  respect.^ 

Sticker,*^  Horbaczewski,^  and  Mendel  and  Jackson^  found  that  the 
excretion  of  uric  acid  is  increased  in  cirrhosis  of  the  liver  in  man. 
Hahn  and  Nencki,^  Nencki,  Pawlow,  and  Zalesky,^"  and  De  Filippi^^ 
found  increased  excretion  of  uric  acid  after  partial  exclusion  of 
the  liver  of  dogs  from  the  circulation  by  Eck's  fistula.  Lieblein  ^^ 
found  increased  excretion  of  uric  acid  in  dogs  after  artificial 
degeneration  of  hepatic  tissue  of  dogs  from  injections  of  acid 
into  the  bile  duct,  and  Horbaczewski  ^  after  degeneration  of 
human  liver  from  phosphorus  poisoning.     Mlinzer,^^  too,  found  no 

1  G.  Salomon.     Zur  Physiologie  der  Xanthinkorper.     Arch,  ftir  Physiol.,  361   (1881). 

2  J.  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xan- 
thinbasen,  sowie  der  Entstehung  der  Leukocytose  im  Saugethierorganismus.  Monatshefte 
fur  Chemie,   12,  221   (1891). 

3  E.  Salkowski.  Ueber  Autodigestion  der  Organe.  Zeitschr.  fiir  klin.  Medizin,  17 
Suppl.,  77  (1890). 

*  Spitzer.  Die  Uberfiihrung  von  Nukleinbasen  in  Harnsaure  durch  die  Sauerstoff- 
libertragende  Wirkung  von  Gewebsausziigen.     Pfliiger's  Archiv,  76,  192  (1899). 

5  H.  Wiener.  Ueber  Zersetzung  und  Bildung  der  Harnsaure  im  Tierkorper.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  42,  375  (1899),  also 

Ibid.  Ueber  Zersetzung  und  Neubildung  der  Harnsaure  im  thierischen  Korper. 
Verhandl.  des  17t  Kongr.  ftir  innere  Med.,  622  (1899). 

^  G.  Sticker.  Beitrage  zur  Pathologie  und  Therapie  der  Lcukamie.  Zeitschr.  fiir 
klin.  Medizin,  14,  80  (1888). 

''  J.  Horbaczewski.  Untersuchungen  liber  die  Entstehung  der  Harnsaure  im  Sauge- 
thierorganismus.    Monatshefte  fur  Chemie,  10,  624  (1889). 

8  L.  Mendel  and  H.  Jackson.  On  Uric  Acid  Formation  after  Splenectomy.  Am.  Journ. 
of  Physiol.,  4,  163  (1900). 

9  Hahn  und  Nencki.     Archives  des  sciences  biologiques  de  St.  Petersbourg,  1,  401  (1892). 
1"  Nencki,   Pawlow,   und   Zalesky.      Ueber   den  Ammoniakgehalt   des   Blutes   und   der 

Organe  und  die  Harnstoffbildung  bei  den  Saugethieren.  Arch,  fur  exp.  Path.  u.  Pharmak., 
37,  49  (1896). 

11  F.  De  FiUppi.  Recherches  sur  I'echange  material  des  chiens  operas  de  fistule  d'Eck. 
Archives  italiennes  de  biologic,  31,  211  (1899),  and 

Jahresber.  tiber  die  Leistungen  und  Fortschritte  in  der  Gesammten  Medicin  (1899). 

12  V.  Lieblein.  Die  Stickstoffausscheidung  nach  Leberveroderung  beim  Saugethiere. 
Arch,  ftir  exp.  Path.  u.  Pharmak.,  33,  318  (1894). 

13  E.  Mtinzer.  Der  Stoffwechsel  bei  akuter  Phosphorvergiftung.  Deutsche  Arch,  fiir 
klin.  Medizin,  52,  199  (1891). 


Physiology  217 

decreased  excretion  of  uric  acid  after  degeneration  of  human  liver 
from  phosphorus  poisoning.  On  account  of  these  facts,  Horbac- 
zewski/  Mendel  and  Jackson,-  and  others  think  that  uric  acid  cannot 
be  formed  in  the  liver,  that  if  the  liver  forms  uric  acid,  we  should 
expect  a  decreased  excretion  of  uric  acid  rather  than  an  increased 
excretion  when  the  functions  of  the  liver  are  interfered  with. 

As  we  shall  see  later,  we  have  fairly  satisfactory  evidence  that 
uric  acid  is  destroyed  by  the  liver  in  dogs.  It  is  probable,  there- 
fore, that  in  dogs,  at  any  rate,  Neumcister's  explanation^  is 
correct.  This  author  believes  that  the  increased  excretion  of 
uric  acid  after  Eck's  fistula  is  due  to  the  fact  that  uric  acid  is 
normally  destroyed  by  the  liver,  and  that  when  the  liver  is  cut 
out  of  the  circulation,  a  larger  quantity  of  uric  acid  than  usual 
escapes  oxidation.  In  the  case  of  man,  the  increased  excretion 
of  uric  acid  in  cirrhosis  of  the  liver  may  be  due  to  oxidation  of 
purin  bases  from  the  nucleoproteid  of  the  nuclei  of  the  degen- 
erated cells,  as  suggested  by  Pick  *  in  the  case  of  dogs  after  in- 
jection of  acid  into  the  bile  duct.  We  have,  then,  no  positive 
indication  that  uric  acid  is  not  formed  in  the  liver. 

Wiener  '"  found  that  uric  acid  is  formed  by  the  autolysis  of  the 
liver,  thymus,  and  spleen  of  the  ox.  Less  uric  acid  is  obtained 
from  the  spleen  and  thymus  than  from  the  liver.  If  chopped-up 
spleen  or  thymus  be  added  to  the  liver,  more  uric  acid  is  obtained 
than  from  either  organ  alone.  Further,  if  an  alcoholic  extract 
of  the  thymus  or  spleen,  which  is  free  from  purin  bodies,  be  added 
to  the  liver,  more  uric  acid  is  obtained  than  from  the  liver  alone. 
Wiener  explains  his  work  by  assuming  that  there  is  some  com- 
pound in  the  thymus  and  spleen  soluble  in  alcohol,  from  which 
uric  acid  can  be  formed  synthetically  by  the  action  of  the  liver. 
It  is  possible  that  the  alcoholic  extract  of  thymus  and  spleen 
contains  something  that  increases  the  rate  at  which  uric  acid  is 
formed  from  the  purin  bases  of  the  cell  nuclei  of  the  liver.  This 
would  explain  Wiener's  results,  for  he  determined  only  the  amount 

1  J.  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xan- 
thinbasen,  sowie  der  Entstehung  der  Leukocytose  im  Saugethierorganismus.  Monatshefte 
fiir  Chemie,  12,  221  (1S91). 

-  L.  Mendel  and  H.  Jackson.  On  Uric  Acid  Formation  after  Splenectomy.  Am. 
Journ.  of  Physiol.,  4,  163  (1900). 

^  Neumeister.     Lehrbuch  der  physiologische  Chemie,  1st  ed.,  part  2,  p.  236. 

*  E.  Pick.  Versuche  iiber  functionelle  Ausschaltung  der  Leber  bei  Saugethieren. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  32,  382  (1893). 

5  H.  Wiener.  Ueber  synthetische  Bildung  der  Harnsaure  im  Thierkorper.  Verhandl. 
des  19t  Kongr.  inuere  lied.,  383  (1901),  and  Hofmeister's  Beitrage,  2,  42  (1902), 


218      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

of  uric  acid  formed  in  four  hours.  Or,  it  may  be  that  the  liver 
normally  oxidizes  as  well  as  forms  uric  acid,  and  that  the  addition 
of  the  alcoholic  extract  of  spleen  and  thymus  partially  inhibits 
the  process  by  which  uric  acid  is  destroyed. 

It  will  be  remembered  that  Wiener  found  that  uric  acid  can  be 
synthesized  in  birds  from  urea  and  certain  dibasic  acids  of  the 
aliphatic  series  and  compounds  allied  to  them.  There  are  three 
of  these,  namely,  tartronic  acid,  glycerin,  and  dialuric  acid, 
which,  when  added  to  chopped-up  ox  liver  undergoing  autolysis, 
cause  the  formation  of  a  larger  quantity  of  uric  acid  than  is 
formed  by  simple  autolysis  of  the  liver  itself.  According  to 
Wiener,  uric  acid  is  synthesized  from  these  three  compounds  by 
the  liver.  We  have  already  seen  Burian's  explanation  of  Wiener's 
results  showing  that  dialuric  and  tartronic  acids  merely  increase 
the  rate  of  the  reaction  by  which  uric  acid  is  formed  from  the 
purin  bodies  of  the  nucleoproteids  of  the  liver  cells. 

Summary 

At  the  present  time  we  believe  that  the  uric  acid  in  the  urine 
comes  from  two  sources,  —  the  purin  bases  in  food  and  those  in  the 
body.  These  purin  bases  in  turn  come  from  the  nucleoproteids 
of  the  cell  nuclei.  Concerning  the  exogenous  nucleoproteids,  all 
we  can  say  is  that  nucleins  can  be  split  off  from  nucleoproteids  by 
the  action  of  pepsin  hydrochloric  acid,  and  that  this  action  may, 
therefore,  take  place  in  the  stomach.  The  autolytic  experi- 
ments on  different  organs  seem  to  indicate  that  most  of  those 
organs  containing  large  amounts  of  nucleoproteids  can  form  uric 
acid.  This,  of  course,  is  e^ndogenous  uric  acid.  It  is  possible 
that  there  is  no  special  organ  in  which  any  of  the  changes  from 
nucleoproteid  to  uric  acid  take  place.  At  any  rate,  we  know 
that  several  enzymes  which  bring  about  the  successive  changes 
from  nucleoproteid  to  uric  acid  are  found  in  many  organs  of  the 
body,  and  it  has  been  suggested  by  Wiener  that  other  organs,  as, 
for  example,  the  liver  of  the  dog,  which  does  not  seem  to  form 
uric  acid,  have  this  power,  but  have  also  the  power  of  oxidizing 
uric  acid  when  once  formed.  We  must  also  bear  in  mind  the 
work  of  Burian  ^  on  the  formation  of  uric  acid  by  active  muscles. 

1  R.  Burian.  Die  Bildung  der  Harnsaure  im  Organismus  des  Menschen.  Med.  Klinik, 
1,  131  (1905). 

Die  Herkunft  der  endogeiien  Harnpurine  bei  Mensch  und  Saugethiere.  Zeit&chr.  fiir 
physiol.  Chem.,  43,  532  (1905). 


Physiology  219 

Organ  of  Decomposition  of  Uric  Acid 
IN    CARXIVORA 

Stokvis  ^  was  the  first  to  observe  that  a  dog's  liver  undergoing 
autolysis  has  the  power  of  destroying  uric  acid.  His  discovery 
has  since  been  confirmed  by  Wiener  ^  and  Jacoby.^  These  authors 
added  uric  acid  to  finely  divided  liver  and  to  the  ac^ueous  extract 
of  liver  and  found  that  the  uric  acid  became  destroyed  in  a  day 
or  so  if  the  mixture  were  left  in  a  warm  place. 

After  Richet  ^  and  Gottlieb '"  found  that  urea  is  formed  during 
the  autolysis  of  dog  liver,  Chassevant  and  Richet  ^  found  that  if 
sodium  urate  be  added  to  the  liver,  it  gradually  disappears  during 
the  process  of  autolysis,  and  that  the  urea  increases.  Richet  ^ 
later  found  that  the  alcoholic  precipitate  of  the  ac|ueous  extract 
of  liver,  containing  probably  purin  bodies,  also  causes  an  increase 
in  the  urea  when  added  to  a  liver  undergoing  autolysis.  These 
authors  did  not  state  the  method  used  for  the  determination  of 
urea. 

Ascoli  ^  obtained  a  similar  result  by  another  procedure.  This 
author  found  that  if  defibrinated  ox  blood  containing  uric  acid 
be  circulated  artificially  through  a  freshly  extirpated  dog  liver, 
the  uric  acid  gradually  disappears  and  urea  appears.  Ascoli 
used  the  Schondorff  ^  method  for  the  determination  of  urea. 

Spitzer  ^^  repeated  the  work  of  Chassevant  and  Richet,  but  could 
not  find  that  the  amount  of  urea  present  in  the  autodigestion  exper- 

'  B.  Stok^as.  Bijdragen  tot  de  physiologic  van  het  acidum  uricum.  Ned.  Tijdschr., 
3,  p.  587,  Afl.,  Oct.  (1859);  Arch.  f.  d.  holl.  Beitr.,  p.  260  (1860),  und  Schmidt's  Jahrb., 
log,  4  (1861). 

2  H.  Wiener.  Zersetzung  und  Neubildung  der  ^Harnsaure  im  thierischen  Korper. 
Verhandl.  des  17  Kongr.  f.  innere  Med.,  622  (1889),  also 

Ibid.  Ueber  Zersetzung  und  Bildung  der  Harnsaure  im  Tierkorper.  Arch,  fiir  e.xp. 
Path.  u.  Pharmak.,  42,  375  (1899). 

3  M.  Jacoby.  Ueber  die  Oxydationsfermente  der  Leber.  Virchow's  Archiv,  157,  235 
(1899). 

■*  C.  Richet.  De  la  formation  d'uree  dans  le  foiejaprfes  la  mort.  Comptes  rendus,  118, 
1125  (1893). 

■'■  GottHeb.  Ueber  Xanthinkorper  im  Harn.  Munchen  med.  Wochenschrift,  42,  7SS 
(1895). 

*  Chassevant  et  Richet.  Des  ferments  solubles  uropoietiques  du  foie.  Comptes  rendus 
de  la  soci<St(?  de  biologie,  10  ser.,  4,  743  (1897). 

^  Richet.     Comptes  rendus  de  la  societe  de  biologie,  368  et  .525  (1894). 

^  G.  Ascoli.  Ueber  die  Stellung  der  Leber  im  Nucleinstoffwechsel.  i  Pfiiiger's  Archiv, 
72,  340  (1898). 

''  B.  Schondorff.  Eine  Methode  der  Harnstoffbestimmung  in  thierischen  Organen  und 
Flussigkeiten.     Pfiiiger's  Archiv,  62,  34  (1896). 

'"  W.  Spitzer.  Weitere  Beobachtungen  iiber  die  oxydativen  Leistungen  thierischer 
Gewebe.     Pfiiiger's  Archiv,  71,  596  (1898). 


220      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

iments  is  increased  by  addition  of  uric  acid  or  urate.  Loewi  ^  re- 
peated this  work  carefully  and  found  that  no  urea  is  formed  from 
uric  acid  in  the  autolj^sis  experiments.  Loewi  used  the  nitric  acid 
test  for  urea.  He  found  that  a  nitrogenous  body,  which  he  de- 
scribed, is  formed  from  the  uric  acid,  and  he  thinks  it  is  an  amido 
acid.  Jacoby  ^  and  Burian  and  Schur  ^  believe  that,  according 
to  the  description,  the  body  called  an  amido  acid  by  Loewi  is 
really  allantoin.  This  seems  very  probable  when  we  remember 
that  uric  acid  is  oxidized  to  allantoin  in  dogs.  Further,  the 
properties  of  allantoin  and  urea  are  similar  in  many  points,  so 
that  the  "  urea  "  of  Chassevant  and  Richet  might  well  have  been 
allantoin.  In  Schondorff's  method  of  determination,  urea,  allan- 
toin, and  alloxantin  are  all  determined  as  urea,  so  that  in  the 
experiments  of  Ascoli,  who  used  this  method,  allantoin  was 
probably  called  urea.  At  any  rate,  some  nitrogenous  body  is 
formed  from  the  uric  acid  in  these  autolysis  experiments  and  it 
is  not  urea.  The  objection,  therefore,  that  we  have  only  an 
apparent  disappearance  of  uric  acid  due  to  the  fact  that  the  de- 
termination of  uric  acid  is  affected  by  the  presence  of  some  of 
the  products  of  autolysis  is  not  valid. 

It  will  be  remembered  that  Stadeler,*  Nencki  and  Sieber,^  and 
Kreidl  "^  found  that  uric  acid  in  alkaline  solution  is  oxidized  by 
the  oxygen  of  the  air  to  uroxanic  acid.  This  might  be  taken  as 
explanation  of  the  disappearance  of  uric  acid  in  the  autotysis 
experiments.  None  of  those  who  performed  these  experiments 
on  the  dog  liver  took  the  precaution  to  do  control  experiments 
after  killing  the  liver  by  boiling.  This  should  be  done,  for  it  is 
not  known  if  uroxanic  acid  could  be  mistaken  for  urea  in  the 
Schondorff  method  for  determining  urea.  Wiener  performed 
control  experiments  in  this  way  on  the  kidney  of  the  ox,  which 
destroys  uric  acid,  and  obtained  negative  results.     It  is  probable, 

^  O.  Loewi.  Ueber  das  harnstoffbildende  Ferment  der  Leber.  Zeitschr.  fvir  physiol. 
Chem.,  25.  511  (1898). 

2  M.  Jacoby.  Ueber  die  Oxydationsferments  der  Leber.  Virchow's  Archiv,  157,  235 
(1899). 

3  R.  Burian  und  IT.  Schur.  L^eber  die  Stellung  der  Purinkorper  im  menschlichen  Stoff- 
wechsel.     2.  Mitth.     Pfliiger's  Archiv,  87,  239  (1901). 

*  G.  Stadeler.  Ueber  die  LTroxansaure,  ein  Zersetzungsprodukt  der  Harnsaure.  Ann. 
d.  Chem.  u.  Pharm.,  78,  286   (1851). 

5  M.  Nencki  und  N.  Sieber.  Ueber  die  Zersetzung  des  Traubenzucker  und  der  Harn- 
saure durch  Alkalien  bei  der  Bluttemperatur.  .Journ.  fiir  prakt.  Chem.  (2),  25,  498 
(1881). 

8  I.  Kreidl.  Bestimmungsmethode  fiir  Harnsaure  und  Beobachtungen  an  Harnsaure- 
losungen.     Monatshefte  fur  Chemie,  14,  109  (1893). 


Physiology  221 

therefore,  that,  in  the  dog  liver,  the  oxidation  process  is  a  vital 
one.  Further,  after  he  confirmed  the  work  showing  that  the 
dog  liver  destroys  uric  acid,  Wiener  ^  showed  that  if  dog  liver 
extract  be  added  to  the  liver  extract  of  an  ox,  which  latter  forms 
uric  acid  from  its  own  material,  the  uric  acid  formed  is  destroyed.^ 
On  standing,  the  amount  of  uric  acid  in  the  mixture  of  dog  liver 
and  ox  liver  diminishes.  This  seems  to  indicate  that  the  de- 
struction of  uric  acid  by  the  dog  liver  is  a  vital  process.  Wiener 
found  also  that  the  dog  kidney  possesses,  to  a  less  extent  than 
the  liver,  the  power  of  destroying  uric  acid. 

That  the  liver  destroys  uric  acid  in  dogs  and  cats  is  indicated 
also  by  the  work  of  Burian  and  Schur.^  These  authors  found 
no  uric  acid  in  the  blood  after  kidney  extirpation  even  when 
thymus  was  fed,  but  did  find  it  when  the  liver  as  well  as  the  kidney 
is  extirpated.  The  absence  of  the  kidney  prevents  the  uric  acid 
from  being  excreted.  The  absence  of  the  liver  prevents  it  from 
being  destroyed.  When  both  organs  are  extirpated,  the  uric 
acid  is  neither  destroyed  nor  excreted.  It  is  stored  up  in  the 
blood. 

It  will  be  remembered  that  Hahn,  Massen,  Nencki,  and 
Pawlow  ^  found  that  after  Eck's  fistula,  there  is  an  increase  in 
the  uric  acid  in  the  urine  of  dogs,  and  that  Lieblein  ^  and 
Pick  ^  obtained  the  same  result  after  liver  necrosis  caused  by 
injecting  acid  into  the  bile  duct.  This  has  been  taken  as  an 
indication  that  the  liver  is  the  organ  in  dogs  which  decom- 
poses uric  acid,^  and  that  when  the  functions  of  the  liver  are 
interfered  with,  less  uric  acid  is  destroyed  than  normally. 
But,  as  we  have  seen,  there  is  another  explanation.  The 
degeneration   of    the  cell  nuclei,  observed  by  Pick,^  would  ac- 

1  H.  Wiener.  Ueber  Zersetzung  und  Neubildung  der  Harnsaure  im  thierischen  Korper. 
Verhandl.  des  17t  Kongr.  fiir  innere  Med.,  622  (1899),  also 

Ihid.  Ueber  Zersetzung  und  Bildung  der  Harnsaure  im  Tierkorper.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  42,  375  (1899). 

2  Ibid.  Ueber  synthetische  Bildung  der  Harnsaure  im  Thierkorper.  Hofmeister's 
Beitrage,  2,  42  (1902). 

3  H.  Burian  und  R.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  menschlichen  Sto£F- 
wechsel.     2.  Mitth.  87,  239  (1901). 

^  n.  Hahn,  O.  Massen,  M.  Nencki,  und  J.  Pawlow.  Die  Eck'sche  Fistel  zwischen  der 
unteren  Hohlvene  und  der  Pfortader  und  ihre  Folgen  fiir  der  Organismus.  Arch,  fur  exp. 
Path.  u.   Pharmak.,  32,   161   (1893). 

^  V.  Lieblein.  Die  Stickstoffausscheidung  nach  Leberveroderung  beim  Saugethieren. 
Arch,  fiir  exp.  Path.  u.  Pharmak.,  33,  318  (1894). 

s  E.  Pick.  Versuche  iiber  functionelle  Ausschaltung  der  Leber  bei  Saugethieren.  Arch, 
fur  exp.  Path.  u.  Pharmak.,  32,  382  (1893). 

'  Neubauer.     Physiologische  Chemie. 


222      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

count  for  this  increased  excretion  of  uric  acid,  so  that  we 
cannot  use  it  as  proof  of  the  fact  that  that  uric  acid  is  de- 
stroyed by  the  Hver  in  dogs.  Yet  Neubauer's.  explanation 
would  account  for  the  fact  noticed  by  Hahn,  Massen,  Nencki, 
and  Pawlow,  that  the  excretion  of  uric  acid  is  especially  high 
on  a  meat  diet  after  Eck's  fistula,  for  we  should  expect  less 
of  the  uric  acid  formed  from  the  hypoxanthin  of  the  meat 
extract  to  be  destroyed  than  when  the  liver  is  present.  It 
may  be  that  Neubauer's  explanation  is  the  correct  one  in  case 
of  Eck's  fistula,  and  Pick's  explanation  in  the  case  of  liver  de- 
generation. A  determination  of  the  allantoin  in  the  urine  of  dogs 
with  Eck's  fistula  and  after  acid  necrosis  of  hepatic  tissue  would 
probably  show  which  theory  is  correct.  According  to  Neubauer's 
theory,  we  should  expect  decreased  allantoin;  according  to  Pick, 
increased  allantoin. 

Pohl  ^  found  that  there  is  no  allantoin  in  the  fresh  organs  of 
the  dog,  but  that  after  undergoing  autolysis  for  several  hours, 
allantoin  is  formed  by  the  mucous  membrane  of  the  alimentary 
canal,  the  liver,  thymus,  the  spleen,  and  pancreas.  The  amount 
of  allantoin  increases  with  the  time.  Allantoin  is  not  formed 
by  the  blood  or  muscle  during  autodigestion. 

Croftan  ^  has  studied  the  decomposition  of  uric  acid  in  dogs 
and  cats.  His  method  of  procedure  was  as  follows:  The  organs 
studied  were  desanguinated,  ground  up  finely,  and  allowed  to 
stand  under  alcohol.  The  alcohol  was  then  filtered  off  and  the 
residue  washed  with  ether  and  allowed  to  dry  in  the  air.  This 
residue  was  finally  extracted  with  water  containing  NaF.  One 
gram  of  uric  acid  was  suspended  in  1,000  cc.  of  water  and  dis- 
solved by  addition  of  Na2C03.  About  100  cc.  of  this  urate  .solu- 
tion was  added  to  the  organ  extract  in  each  case.  Three  solutions, 
I,  II,  and  III,  were  prepared  in  this  way.  In  flask  I  the  uric  acid 
was  determined  immediately.  The  contents  of  flask  II  were 
heated  to  boiling  and  allowed  to  stand  at  38°  C.  for  forty-eight 
hours.  The  contents  of  flask  III  were  not  boiled,  but  were 
allowed  to  stand  at  38°  C.  for  forty-eight  hours.  The  uric 
acid  in  flasks  II  and  III  was  determined  at  the  end  of  forty- 
eight   hours.      In    flask    II    the    boiling    destroys  the  ferment. 

1  J.  Pohl.  Ueber  Allantoinausscheidung  bei  Intoxicationen.  Arch,  fiir  exp.  Path.  u. 
Pharmak.,  48,  367  (1902). 

2  A.  Croftan.  Synopsis  of  experiments  on  the  transformation  of  circulating  uric  acid 
in  the  organism  of  man  and  animals.     Med.  Record,  64,  6  (1903). 


Physiology  223 

Flask  II,  then,  acts  as  a  check  on  flask  III.     The  results  are 
shown  in  the  table. 

I  II  I— TI  III  I— III  destroyed 

liver 0.327  0.325  0.002  0.225  0.102  31.1 

kidney 0.319  0.319  0.000  0.312  0.007  2.4 

Dog      ( muscle 0.330  0.326  0.004  0.303  0.027  8.2 

blood 0.321  0.317  0.004  0.313  0.008  2.5 

spleen 0.327  0.320  0.007  0.319  0.008  2.4 

liver 0.331  0.326  0.005  0.239  0.092  28.0 

kidney 0.327  0.326  0.001  0.318  0.009  2.6 

Cat        ( muscle 0.316  0.310  0.006  0.291  0.025  7.8 

blood 0.316  0.314  0.002  0.305  0.011  2.6 

spleen 0.332  0.328  0.004  0.326  0.006  1.9 

It  will  be  seen  that  the  liver  is  the  most  active  organ  in  the 
destruction  of  uric  acid.  The  muscles  also  have  some  uric  acid 
destroying  power.  Croftan  has  suggested  that  while  weight  for 
weight  the  liver  is  more  active  than  muscles,  the  latter  may  be 
more  important,  physiologically,  on  account  of  their  much  greater 
bulk.  The  results  in  the  case  of  the  other  organs  do  not  seem  to 
show  much  greater  destruction  than  the  check  experiments. 

Croftan  went  further  and  studied  the  ferment,  which,  he  says, 
though  he  does  not  give  the  details  of  his  work,  consists  of  a 
nucleoproteid,  an  albumose  which  is  powerless  alone,  and  certain 
salts  which  hold  the  albumose  in  solution.  He  states  that  the 
albumose  is  probably  the  specific  agent,  for  the  nucleoproteid 
is  found  universally  in  those  organs  which  do  not  destroy  uric 
acid.  The  nucleoproteid  has  the  power  of  dissociating  II2O2  and 
giving  out  oxygen,  and  therefore  probably  acts  as  a  carrier  of 
oxygen  in  the  process.  He  finds  that  certain  salts,  for  example, 
nitrates  and  cyanates,  diminish  the  power  of  the  nucleoproteid 
to  liberate  oxygen.  Other  compounds,  for  example,  alkalies  and 
salicylates,  greatly  increase  it.  The  author  suggests  that  good 
effect  of  alkalies  and  salicylates  in  gout  may  be  connected  with 
this  action. 

IN  OTHER  MAMMALS 
According  to  Stokvis,^  if  uric  acid  is  added  to    horse    liver 
undergoing   autolysis,   the   uric   acid   is   destroyed.     The   swine 

1  B.  Stok-\-is.  Bijdragen  tot  de  physiologie  van  het  aeidum  uricum.  Ned.  Tijdschr., 
3,  p.  587,  Afl.,  Oct.  (1859) ;  Arch.  f.  d.  holl.  Beitr.,  260  (1860),  and  Schmidt's  Jahrh.,  109, 
4  (1861). 


224      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

liver,  also,  according  to  Wiener  ^  destroys  uric  acid  when  under- 
going autolysis.  Wiener  ^  found,  too,  that  the  kidney  of  the 
horse  and  ox  destroy  uric  acid,  and  that  's  is  a  vital  process 
destroyed  by  boiling.     Lang  ^  and  Schittei  likewise  found 

that  the  liver  and  kidney  of  the  ox  can  de^;  ,  ,  m  acid.     Lang  ^ 

found,  too,  that  the  spleen  and  intestinal  ^  all  can  destroy  uric 
acid. 

Wiener,^  Lang,^  Schittenhelm,^  and  Burir  have  shown  that 
muscle  is  capable  of  destroying  uric  acid.  ilthough  the  power 
of  the  ox  muscle  for  destroying  uric  acid  is  less  than  that  of  the 
kidney,  Wiener  thinks  that  on  account  of  the  greater  quantity 
of  muscle  in  the  body  it  may  be  of  more  importance  in  the  oxi- 
dation of  uric  acid  than  the  kidneys. 

Ascoli  ^  found  that  ox  blood  destroys  uric  acid  during  autolysis. 

Cippolina  "  found  more  oxalic  acid  in  the  liver  and  spleen  of  the 
ox  and  calf  after  they  had  undergone  autolysis  for  a  few  hours  if 
uric  acid  had  been  previously  added  than  if  the  uric  acid  were  not 
added.  He  assumed  that  the  uric  acid  is  oxidized  to  oxalic  acid, 
and  therefore  that  the  liver  and  spleen  of  the  ox  and  calf  are  the 
organs  in  which  the  oxidation  takes  place.  We  have  seen,  how- 
ever, that  it  is  doubtful  if  oxalic  acid  is  formed  in  the  body  as  an 
oxidation  product  of  uric  acid.  Further,  it  has  been  shown  by 
W^iener  that  the  uric  acid  content  of  the  liver  and  spleen  of  the 
ox  and  calf  increases  during  autolysis,  that,  therefore,  these  organs 
form  uric  acid.  He  has  suggested,  however,  that  both  formation 
and  destruction  of  uric  acid  may  go  on  at  the  same  time  in  the 
various  organs,  and  that  whether  the  increase  in  uric  acid  is 
positive  or  negative  in  any  organ  depends  on  whether  the  process 
of  formation  or  process  of  destruction  is  more  active.  He  has, 
in  fact,  shown  that  under  certain  conditions  even  the  liver  of  the 

^  H.  Wiener.  Ueber  Zersetzung  und  Neubildung  der  Harnsaure  im  thierischen  Korper. 
Verhandl.  des  17t  Kongr.  fiir  innere  Med.,  622  (1899),  also 

Ibid.  Ueber  Zersetzung  und  Bildung  der  Harnsaure  im  Tierkorper.  Arch,  fiir  exp. 
Path.  u.  Pharmak.,  42,  375  (1899). 

2  S.  Lang.  Ueber  desamidierung  im  Tierkorper.  Hofmeister's  Beitrage,  5,  321 
(1904). 

3  A.  Schittenhelm.  Ueber  die  Fermente  des  Nukleinstoffwechsels.  Zeitsohr.  fiir  physiol. 
Chem.,  43,  228  (1904). 

^  R.  Burian.  Die  Herkunft  der  endogenen  Harnpurine  bei  Mensch  und  Saugethiere. 
Zeitschr.  fiir  physiol.  Chem.,  43,  532  (1905). 

5  G.  Ascoli.  Ueber  die  Stellung  der  Leber  im  Nukleinstoffwechsel.  Pfliiger's  Archiv, 
72,  340  (1898). 

*  Cippolina.  L^eber  die  Oxalsaure  im  Organismus.  Berl.  klin.  Wochenschrift,  38,  544 
(1901). 


Physiology 


225 


dog  can  form  uric  acid,  and  Burian  ^  has  shown  that  the  liver  of 
the  ox  can  destroy  uric  acid. 

Croftan  performed  experiments  with  the  organs  of  herbivora 

and  omnivora,  as  w''""'^':ls  those  of  dogs  and  cats.  The  method  of 
experimenting  h  ''  '"''■''fPexplained  a  few  pages  back.  The  results 
are  shown  in  th^4:   ^ ^'M^hg  table: 

r  ■"  Per  cent 

I                II  I— II  III  I— III  destroyed 

!                   (liver 0.331      0.327  0.004  0.322  0.009       2.7 

^^^         I  kidney   '  ilJti:.. 0.321      0.316  0.005  0.236  0.085     26.4 

)  muscle.:  A 0.327      0.321  0.006  0.305  0.022       6.8 

Upleen 0.313      0.309  0.004  0.306  0.007       2.1 

/liver.  ..,!.!. 0.314      0.309  0.005  0.306  0.008       2.6 

\  kidney... 0.316      0.314  0.002  0.239  0.077     24.3 

Rabbit    (muscle 0.331      0.324  0.007  0.311  0.020       6.0 

(blood 0.324      0.322  0.002  0.317  0.007       2.2 

^spleen 0.321      0.317  0.004  0.314  0.007       2.2 

[liver 0.332      0.326  0.006  0.238  0.094     28.2 

J  kidney 0.326     0.321  0.005  0.247  0.079     24.2 

[^°§          j  muscle 0.318      0.317  0.001  0.299  0.019       6.2 

§\                   (spleen 0.331      0.324  0.007  0.325  0.008       2.4 

>  J 

1  I                  [liver 0.319      0.314  0.005  0.200  0.119     37.4 

oj                   \  kidney 0.327      0.325  0.002  0.188  0.139     42.6 

Man         /muscle 0.322      0.319  0.003  0.299  0.023       7.2 

spleen 0.332      0.324  0.006  0.325  0.007       2.2 

blood 0.326      0.320  0.006  0.318  0.008       2.6 


It  will  be  seen  that  while  in  carnivora  the  liver  is  the  most 
active  organ,  in  herbivora  the  kidneys  are  the  most  active.  In 
omnivora  both  the  liver  and  the  kidneys  are  active  in  destroying 
uric  acid.  In  all  cases  the  muscles  are  active  to  about  the  same 
extent. 

Wiener  ^  has  stated  that  he  obtained  the  uric  acid  destroying 
ferment  free  from  cells.  His  experiments  are  not  yet  concluded, 
however. 

Summary 
Our  knowledge  concerning  the  destruction  of  uric  acid  in  the 
body  depends  chiefly  on  observations  on  the  autolytic  action  of 
isolated  organs.     While  it  is  not  absolutely  correct  to  draw  from 

'  R.  Burian.  Ueber  die  Oxydative  und  die  vermeintliche  synthetische  Bildung  von 
Harnsiiure  in  Rinderleberauszug.     Zeitschr.  fiir  physiol.  Chem.,  43,  497  (1905). 

2  H.  Wiener.  Ueber  Harnsaurezersetzung  durch  Organferment.  Centralblatt  fur 
Physiol.,    18,   690   (1904). 


226       The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

these  experiments  alone  conclusions  concerning  the  action  of 
the  organs  when  they  form  a  part  of  the  living  organ,  yet  it  seems 
probable  that  uric  acid  is  destroyed  by  the  liver  in  carnivora,  and 
to  a  lesser  extent  by  the  muscles,  and  perhaps  also  by  the  thymus, 
spleen,  pancreas,  and  kidney,  by  the  kidneys  in  herbivora,  and  by 
both  the  kidneys  and  liver  in  omnivora. 

The  Effect  of  Drugs  on  the  Metabolism  of   Uric  Acid 

In  speaking  of  the  therapeutics  in  gout,  Minkowski  ^  says  "  that 
whatever  may  be  the  interpretation  of  the  pathological  processes  in 
different  instances,  the  aims  of  therapeutics  may  be  divided  into 
three  classes: 

"1.  Treating  the  primary  defects  in  the  metabolism. 

"■  2.  Influencing  especially  the  metabolism  of  the  uric  acid. 

"3.  Treating  the  individual  symptoms  in  different  cases." 

This  evidently  covers  the  field  of  therapeutics  in  gout. 

As  we  shall  see  later,  we  do  not  know  at  present  in  what  way 
the  metabolism  in  gout  is  abnormal.  So  far,  then,  scientific 
medicine  has  nothing  to  offer  in  the  way  of  a  direct  treatment 
of  the  fundamental  disturbances  in  the  metabolism  of  gout. 
Clinical  observation  has  shown  the  deleterious  influence  of  high 
living,  abuse  of  alcohol,  lack  of  exercise,  and  lead  poisoning,  and 
the  good  effect  of  certain  drugs,  frugal  living,  exercise,  massage, 
and  bathing  on  gout.  There  are,  therefore,  indirect  methods  of 
treatment  of  the  first  class,  but  as  these  methods  belong  to  the 
field  of  clinical  medicine,  they  will  not  be  considered  here.  The 
methods  of  treating  the  individual  symptoms  in  different  cases 
of  gout  belong  also  to  the  field  of  clinical  medicine. 

In  regard  to  influencing  the  metabolism  of  uric  acid,  Minkowski 
says  that  we  should  "  endeavor  to  prevent  the  body  from  becoming 
highly  charged  with  uric  acid."  He  gives  four  methods  of  doing 
this,  viz.: 

(a)   By  decreasing  the  formation  of  uric  acid. 

(6)   By  furthering  the  excretion. 

(c)   By  hastening  the  further  oxidation. 

{d)  By  increasing  the  solubility  of  the  uric  acid  in  the  blood 
and  tissues. 

1  More  or  less  literal  from  Minkowski.  Die  Gicht,  p.  271.  Specielle  Pathologie  und 
Therapie  von  H.  Nothnagel,  Bd.  7,  Tli.  3  (1903). 


Physiology  '221 

There  is  some  doubt  whether,  in  treating  gout,  there  is  any 
value  in  bringing  about  these  results  spoken  of  by  Minkowski. 
This  point  will  be  taken  up  later  in  the  section  on  gout.  But  in 
this  chapter  we  shall  see  how  we  can  bring  about  the  result 
stated  under  (a),  (6),  (c),  and  {d)  by  drugs,  for  it  is  very  generally 
considered  that  we  should  try  to  have  as  little  uric  acid  formed 
as  possible  in  gouty  people,  and  to  rid  the  organism  of  it  as 
rapidly  as  possible.  Ebstein^  has,  in  fact,  defined  the  uric  acid 
diathesis  as  "  a  pathological  disposition  of  man  in  consequence 
of  which,  without  known  functional  or  organic  primary  disturb- 
ance, more  uric  acid  is  formed  than  normally." 

Under  the  head  of  the  so-called  uric  acid  diathesis  there  is 
another  abnormal  tendency,  that  of  forming  uric  acid  calculi  and 
gravel.  In  speaking  of  the  treatment  of  this  tendency,  von 
Noorden^  says  that  we  should  (1)  give  large  quantities  of  water 
to  increase  the  dissolving  power  of  the  urine  for  uric  acid;  (2) 
give  such  food  as  gives  rise  to  little  uric  acid;  (3)  administer  drugs 
which,  after  passing  through  the  body,  make  the  urine  a  better 
solvent  for  uric  acid;  (4)  keep  out  of  the  food  substances  which, 
after  passing  through  the  body,  make  the  urine  a  poor  solvent  for 
uric  acid. 

The  value  and  the  uselessness  of  these  various  methods  of 
influencing  the  metabolism  of  uric  acid  will  be  discussed  later. 
We  have  already  seen  the  effects  of  different  kinds  of  foodstuffs 
on  the  formation  of  uric  acid.  There  remains  to  be  considered 
the  effect  of  drugs  and  large  quantities  of  water  on  the  dissolving 
power  of  the  urine  and  blood  for  uric  acid,  and  of  the  effect  of 
drugs  on  the  formation  of  uric  acid. 

The  Effect  of  Drugs  on  the  Solubility  of  Uric  Acid  in  the  Urine 

In  cases  of  uric  acid  stones  and  gravel,  one  of  the  chief  aims  of 
therapeutics  has  been  to  make  the  urine  a  better  solvent  for  uric 
acid.  The  patient  is  sometimes  recommended  to  drink  large 
quantities  of  water.  In  cases  in  which  onl}^  a  slight  precipitation 
of  uric  acid  occurs  in  the  warm  urine,  we  might  succeed  in  holding 
a  larger  quantity  of  uric  acid  in  solution  by  greatly  increased 
diuresis,  but  in   a  solution   of  uric   acid   so  highly  saturated  as 

'  Ebstein.     Die  Natur  und  Behandlung  der  Harnsteine.     Wiesbaden,  1SS4. 
2  C.  ,v.   Noorden.      Zur  Behandlung  der   harnsauren   Nierenconcremente.      Verhandl. 
des  14t  Kongr.  fur  innere  Med.  (1896). 


228      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

urine,  we  should  scarcely  expect  to  dissolve  much  of  the  gravel 
already  formed  by  increased  diuresis,  especially  since  the  gravel 
and  stones  are  usually  somewhat  protected  from  solution  by 
the  organic  material  which  covers  them.  Large  quantities  of 
urine  would  probably  act  as  a  good  mechanical  agent  in  washing 
out  gravel. 

The  alkalies  have  always  been  highly  recommended  in  the 
treatment  of  uric  acid  calculi.  The  theory  has  been  that  since 
the  salts  of  uric  acid  are  more  soluble  than  uric  acid  itself,  alkalies, 
or  compounds  which  change  to  alkalies  on  passing  through  the 
body,  would  make  the  urine  less  acid,  and  would  also  give  uric 
acid  as  a  soluble  salt  rather  than  the  insoluble  free  acid.  In 
treating  the  subject  of  uric  acid  in  the  urine,  we  have  already 
seen  how  this  view  must  be  considerably  modified.  The  con- 
clusions arrived  at  in  that  part  of  the  book  were  that  determina- 
tions of  the  acidity  of  the  urine  by  titration  methods  were  entirely 
unreliable,  that  facts  concerning  the  behavior  of  cold  urine 
do  not  apply  to  urine  at  the  body  temperature,  that  the  action 
of  alkalies  on  a  normal  urine  at  the  body  temperature  is  different 
from  the  action  of  alkalies  on  a  urine  from  which  the  gravel 
deposits  at  37°,  and  finally  that  the  administration  of  alkalies 
in  quantities  insufficient  to  make  the  urine  almost  alkaline 
cannot  affect  the  solubility  of  uric  acid. 

Tunicliffe  and  Rosenheim  ^  found  that  certain  of  the  organic 
bases  —  and  inorganic  bases  would  undoubtedly  have  acted  in 
the  same  way  —  made  normal  urine  at  the  body  temperature 
a  much  better  solvent  for  uric  acid  than  the  urine  itself.  As 
we  have  already  seen,  however,  urine  from  which  uric  acid  de- 
posits at  the  body  temperature  corresponds  in  this  respect  at 
the  body  temperature  to  normal  urine  at  the  room  temperature, 
and  therefore  alkalies,  unless  added  in  quantities  sufficient  to 
decrease  very  considerably  the  acidity  as  determined  by  titration, 
can  have  little  effect  on  the  dissolving  power  of  the  urine  for  uric 
acid.  When  alkali  enough  is  given  to  make  the  urine  almost 
alkaline  at  the  body  temperature,  we  should  expect  that  even  a 
urine  which  deposits  uric  acid  would  be  a  better  solvent  than  it 
ordinarily  is  in  uric  acid.  It  is  doubtful  if  a  nearly  saturated 
'  solution  of  uric  acid,  such  as  urine,  even  when  it  is  nearly  alkaline, 

1  F.  Tunicliffe  and  D.  Rosenheim.  Piperidine  as  a  Uric  Acid  Solvent,  a  comparative 
study.     Lancet  (1898),  2,  198. 


Physiology  229 

will  have  much  effect  on  uric  acicl  which  is  once  precipitated, 
especially  since  the  crystals  are  somewhat  protected  by  a  covering 
of  mucous-like  organic  material. 

The  inorganic  alkalies,  the  carbonates  of  lithium,  sodium,  and 
potassium,  the  bicarbonate  of  sodium,  and  CaHoCCOa)^  and 
mineral  waters  containing  these  bodies  have  been  used  longest 
as  uric  acid  solvents.  Pfeiffer  ^  found  after  use  of  LiCOg,  NajCOg, 
or  the  alkaline  Carlsbad  Muhlbrunnen  water,  that  less  uric 
acid  is  given  up  to  the  uric  acid  filter  than  before  using  the  water. 
This  is  what  we  should  expect.  According  to  our  explanation  of 
the  behavior  of  uric  acid  in  the  urine,  and  of  Pfeiffer's  results, 
the  addition  of  alkali  should  influence  the  equilibrium  between 
uric  acid  and  the  other  acid  bodies  in  the  urine  in  such  a  direc- 
tion that  less  uric  acid  is  precipitated  on  the  uric  acid  filter  than 
before  adding  the  alkali.  But  we  cannot  conclude  from  Pfeiffer's 
results  that  in  a  urine  which  tends  to  deposit  gravel  we  can  pre- 
vent the  deposition  by  administration  of  alkaline  waters.  Pfeiffer  ^ 
found  later  that  Fachinger  water  which  contains  CaH2(C03)4  acts 
like  the  other  alkalies  in  this  respect.  As  we  should  expect  from 
theoretical  considerations,  Pfeiffer  ^  found  that  water  containing 
chiefly  only  NaCl  (Wiesbadener  Kochbrunner)  has  no  influence 
on  the  dissolving  power  of  the  urine  for  uric  acid.  The  decrease  of 
the  "  free  "  uric  acid  by  NaoCOg  has  been  confirmed  by  Neumayer.^ 

CaCOg  and  CaH2(C03)4  have  also  been  recommended  by  v. 
Noorden  *  and  others  because  of  their  belief  that  these  compounds 
increase  the  ratio  alkaline  sodium  phosphate  :  acid  sodium  phos- 
phate. Ritter  ^  had  shown  that  a  high  value  for  this  ratio  has 
a  favorable  influence  on  the  solvent  power  of  the  urine  for  uric 
acid. 

Rosenfeld  ^  could  not  find  that  alkalies  have  any  influence  on 
the  solvent  power  of  the  urine  for  uric  acid. 

1  Fi.  Pfpjfff-r.  ^  Zur  Aetiologie  und  Therapie  der  Gicht.  Verhandl.  des  5t  Kongr.  fur 
innere  Med.,  444   (1886). 

2  Ibid.  Zur  Behandlung  verscheidener  Nierenkrankungen.  Berl.  klin.  Wochenschrift, 
27,   445   (1890),  and 

Ibid.  Ueber  Harnsaure  und  Gicht.  Berl.  klin.  Wochenschrift,  29,  383,  412,  461,  490, 
und  536  (1892). 

3  H.  Neumayer.    Discussion  in  d.  Versamml.  des  14t  Kongr.  fiir  innere  Med.,  424  (1896). 
^  V.   Noorden.     Zur  Behandlung  der  harnsauren   Nierenconcremente.     Verhandl.   des 

14t  Kongr.  fur  innere  Med.   (1896). 

5  A.  Ritter.  Ueber  die  Bedingungen  fur  die  Entstehung  harnsiiurer  Sedimente,  ein 
Beitrag  zur  Theorie  der  Gicht.     Zeitschr.  fiir  Biol.,  35,  155  (1897). 

•^  G.  Rosenfeld.  Grundzvige  der  Behandlung  der  harnsauren  Diathese.  Verhandl.  des 
14t  Kongr.  fiir  innere  Med.,  318  (1896). 


230      The  Chemistry,  Physiology  and  Pathology  of  Uric  Acid 

The  experiments  of  Schreiber  and  Zaudy  ^  indicate  that  alkalies 
very  slightly  increase  the  solubility  of  the  uric  acid  in  the  urine. 
Meisls  ^  added  Li  CO3  to  a  urine  and  found  that  the  solvent  power 
of  the  urine  for  uric  acid  is  not  increased.  Ortowski  ^  tested 
carefully  the  action  of  addition  of  NaHCOg  to  urine  on  its  power 
of  dissolving  uric  acid,  and  found  that  there  is  no  effect.  The 
inorganic  alkalies,  then,  seem  to  have  little  effect  on  the  solubility 
of  uric  acid  in  cold  urine. 

The  organic  bases,  piperazin,  lysidin,  piperidine,  lycetol,  have 
been  introduced  as  therapeutic  agents  in  uric  acid  gravel  and 
stones  on  account  of  the  fact  that  the  urates  of  these  bases  are 
even  more  soluble  than  the  urates  of  the  inorganic  alkalies.* 

Biesenthal  and  Schmidt  ^  and  Majert  and  Schmidt  ^  found  that 
a  dilute  aqueous  solution  of  piperazin  dissolves  uric  acid  in 
large  amounts.  Biesenthal  and  Schmidt  ^  therefore  recommended 
piperazin  in  cases  of  uric  acid  calculi,  and  stated  that  they  ob- 
tained good  clinical  results  from  it  in  such  cases. 

Mendelsohn  ^  and  Meisls  ^  confirmed  the  observations  showing 

1  Schreiber  und  Zaudy.  Zur  Wirkungen  der  Offenbacher  Kaiser  Friedrichs-Quelle. 
Zeitschr.  fur  diiit-  und  physikal.  Therapie,  2,  136  (1899). 

^  W.  Meisls.  Experimente  mit  Piperazin  und  anderen  uratlosenden  Mitteln.  Ungar- 
isches  Arch,  fiir  Med.,  1,  364  (1893).  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thier- 
chemie,  23,  582  (1893). 

3  W.  Ortowski.  Vergleichende  Untersuchungen  iiber  Urotropin,  Piperazin,  Lysidin, 
Uricedin,  und  Natron  bicarbonicum  bei  der  harnsauren  Diathese.  Zeitschr.  fiir  klin. 
Med.,  40,  331  (1900). 

/CH2-CH2\ 

*  Piperazin  is  diethylendiamin  NH  NH 

\  CH2  —  QYio^ 

N   —   CH2 
II  I 

Lysidin  is  ethylenethylenyldiamin,  C  CH2 

/    \    / 
CH3      NH 

CH2 
/       \ 

CH,  CH2 

Piperidine  is    |  |  lycetol  is  dimethylpiperazin  (dipropylendiamin). 

CH,  CH2 

\        / 
NH 
s  Biesenthal  und  Schmidt.     Piperazin  bei  Gicht  und  Steinleiden.     Berl.  klin.  Wochen- 
schrift,  28,  1214,  and  1231  (1891). 

6  W.  Majert  und  A.  Schmidt.  Ueber  das  Piperazin.  Ber.  der  Dtsch.  chem.  Gesell., 
23,  3722  (1890). 

^  Biesenthal  und  Schmidt.  Klinisches  iiber  das  Piperazin.  Berl.  klin.  Wochenschrift, 
29,  28  (1892). 

8M.  Mendelsohn.  Uber  Harnsaurelosung,  insbesondere  durch  Piperazin.  Berl.  klin. 
Wochenschrift,  29,  381  (1892),  also 

Ihid.  M.  Mendelsohn  in  discussion  of  P.  Bies.enthal's  article,  Praparate  kiinstlicher 
Gicht  und  Praparate  geheilter  klinstHcher  Gicht.  Berl.  med.  Gesell.,  19  July,  1893;  Berl. 
klin.  Wochenschrift,  30,  830  (1893). 


Physiology  231 

that  an  aqueous  solution  of  piperazin  dissolves  uric  acid,  but 
found  that  a  urinary  solution  of  piperazin  does  not  dissolve  uric 
acid,  Ortowski  ^  confirmed  the  experiments  of  Mendelsohn  and 
Meisls  on  piperazin,  and  found  that  lysidin  and  uricedin  behave 
in  the  same  way,  that  is,  an  aqueous  solution  dissolves  uric  acid, 
a  urinary  solution  does  not.  Meisls,^  too,  found  that  a  urinary 
solution  of  uricedin  does  not  dissolve  uric  acid  stones.  Mendel- 
sohn,^ Ortowski,^  and  Casper  ^  found  further  that  the  urine  of 
patients  to  whom  piperazin  has  been  given  does  not  dissolve 
uric  acid  stones.  Casper  ^  found  the  same  true  for  lysidin,  and 
Ortowski  ^  for  lysidin  and  uricedin.  Mendelsohn  ^  found  that 
even  an  aqueous  piperazin  solution  takes  a  long  time  to  dissolve 
bladder  stones  of  uric  acid.  He  did  not  find  this  drug  of  any 
clinical  value  in  uric  acid  calculi.^  Goodbody  ^  is  the  only  ex- 
perimenter who  states  that  piperazin  or  lysidin  makes  urine  a 
better  solvent  for  uric  acid.  His  results  do  not  show  this,  how- 
ever. The  amount  of  uric  acid  excreted  is  about  the  same  in 
both  cases.  Weintraud  ^  could  not  find  that  the  administration 
of  lysidin  has  any  effect  on  the  precipitation  of  uric  acid.  The 
statement  of  Ewald  *  that  sidonal  (the  quinic  acid  salt  of  piper- 
azin) and  of  Grawitz  ^  and  others  that  lysidin  is  clinically  good  in 
cases  of  uric  acid  stones  and  gravel  cannot  be  accepted  as  evidence 
of  the  chemical  action  of  these  compounds,  whatever  clinical  value 
they  may  have. 

As  we  have  seen,  we  should  not  expect  that  the  alkalies,  or- 
ganic or  inorganic,  Avould  have  any  effect  on  the  dissolving  power 
of  cold  urine  for  uric  acid  when  uric  acid  normally  precipitates 

1 W.   Ortowski.     Vergleichende  Untersuchungen  iiber  Urotropin,   Piperazin,   Lysidin, 
Uricedin,   und   Natron   bicarbonicum   bei   der   harnsauren    Diathese.     Zeitschr.   fiir   klin. 
Med.,  40.  331  (1900). 
,     2  w_  Meisls.     Einige  Versuche  mit  Uricedin.     Pester  med.-chir.  Presse.,  30,  684  (1894). 

3  M.  Mendelsohn.  Ueber  Harnsaurelosung  insbesondere  durch  Piperazin.  Berl.  klin. 
Wochenschrift,  29,  384  (1892). 

*  L.  Casper.  Ueber  einiger  Eigenschaften  und  Indikationen  des  Urotropins.  Deutsche 
med.  Wochenschrift,  Ther.  Beit.,  75  (1897). 

5  M.  Mendelsohn.  Discussion  of  P.  Biesenthal's  article,  Praparate  kiinsthcher  Gicht 
und  Praparate  geheilter  kiinstlicher  Gicht.  Berl.  med.  GeselL,  19  July,  1893;  Berl  klin. 
Wochenschrift,  30,  830  (1893). 

^  F.  Goodbody.  The  action  of  lysidin  and  piperazin  as  uric  acid  solvents.  Brit. 
Med.  Journ.   (1896),  II,  901. 

'  W.  Weintraud.  Ueber  die  Einfluss  des  Nucleins  der  Nahrung  auf  die  Harnsaure- 
bildung,  32,  405  (1895). 

*  Ewald.  Discussion  of  Blumenthal's  article,  Ueber  Sidonal,  ein  neues  Gichtmittel. 
Verhandl.  des  Vereins  fiir  innere  Med.,  Berl.,  19,  480  (1899-1900). 

"  E.  Grawitz.  Beobachtungen  iiber  ein  neues  harnsaurelosendes  Mittel.  Deutsche 
med.  Wochenschrift,  20,  786  (1894). 


232      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

from  it.  The  only  effect  would  be  to  decrease  the  amount  of 
uric  acid  which  is  precipitated  before  equilibrium  is  reached. 
Neumayer  ^  has,  in  fact,  shown  that  the  administration  of  lysidin, 
or  NaoCOg  decreases  the  free  uric  acid.  For  therapeutic  ends, 
however,  it  is  the  dissolving  power  of  urine  for  uric  acid  at  the 
body  temperature  that  we  wish  to  affect.  We  have  seen  that 
Tunicliffe  and  Rosenheim^  showed  that  the  addition  of  piperidine, 
piperazin,  or  lysidin  to  a  normal  urine  increases  its  dissolving 
power  for  uric  acid  at  the  body  temperature.  But  a  urine  which 
deposits  uric  acid  while  still  warm  in  the  body  is  comparable 
in  this  respect  with  a  cold  normal  urine.  This  is  the  kind  of 
urine  with  which  we  have  to  deal  in  cases  of  uric  acid  gravel. 
Alkalies,  then,  unless  in  large  quantities,  have  almost  no  effect 
on  the  dissolving  power  of  such  a  urine  for  uric  acid  even  at  the 
body  temperature. 

According  to  Neumayer,^  beer  and  white  wine  decrease  the 
solvent  power  of  the  urine  for  uric  acid;  red  wine  and  pure  alcohol 
have  no  effect. 

It  will  be  well  to  speak  here  of  Haig's  *  views  concerning  the 
uric  acid  in  the  urine.  According  to  this  author,  the  quantity 
of  uric  acid  in  the  urine  varies  inversely  as  the  acidity.  By  the 
quantity  of  uric  acid,  Haig  means  the  value  of  the  ratio  of  the 
quantity  of  uric  acid  to  the  quantit}^  of  urea.  With  our  present 
knowledge  of  the  metabolism  of  uric  acid,  we  can  see  that  the 
quantity  of  each  of  these  substances  can  be  varied  independently 
by  controlling  the  food,  so  that  the  physiological  significance  of 
the  value  of  this  ratio  can  be  but  little.  Haig  used  the  inaccurate 
Hay  craft  method  for  determining  uric  acid,  and  an  inaccurate 
method  for  the  determination  of  the  acidity  of  the  urine,  so  that 
we  can  place  but  little  dependence  upon  his  results. 

Herringham  and  Davies  ^  could  find  no  relation  between  the 
acidity  of  urine  (determined  by  titration)  and  the  value  of 
the  ratio  uric  acid  :    area.      They  used   the   Salkowski  method 

1  H.  Neumayer.  Discussion  in  d.  Versammlung  des  14t  Kongr.  fiir  innere  Med.,  424 
(1896). 

2  F.  Tunicliffe  and  O.  Rosenheim.  Piperidine  as  a  Uric  Acid  Solvent,  a  comparative 
study.     Lancet  (1898),  2,  198. 

3  H.  Neumayer.  Ueber  die  Therapie  der  harnsauren  Diathese.  Verhandl.  des  aerzt- 
licher  verein  in  Munchen,  9  Marz,  1898.  Deutsche  med.  Wochenschrift,  24,  vereins  Beilage, 
60  (1898). 

*  Haig.     Uric  Acid  as  a  Factor  in  the  Causation  of  Disease.     London,  1896. 
5  W.  Herringham  and  H.  Davies.     On  the  Secretion  of  Uric  Acid  and  Urea.    Journ.  of 
Physiol.,  12,  475  (1891). 


.<»* 


Physiology  233 

for  the  determination  of  uric  acid.  Herringham  and  Groves,^ 
Schreiber  and  Waldvogel,^  Sclireiber  and  Zaiidy,^  and  Strauss  * 
found  tliat  there  is  no  constant  relation  between  the  quantity 
of  uric  acid  in  the  urine  and  the  acidity  of  the  urine  (determined 
by  titration).  We  should,  of  course,  expect  that  the  quantity 
of  uric  acid  in  the  urine  and  the  acidity  of  the  urine  could  be 
varied    independently. 

The  poor  results  obtained  from  the  alkalies  in  the  treatment 
of  uric  acid  gravel  and  calculi  has  led  to  the  use  of  certain  drugs 
which  unite  with  uric  acid  to  form  organic  compounds  which 
are  not  salts  and  which,  therefore,  will  hold  the  uric  acid  in  solu- 
tion even  in  an  acid  urine.  The  first  of  this  class  of  bodies  to 
be  used  was  urea.  On  the  basis  of  Riidel's  ^  statement  that  urea 
forms  a  compound  with  uric  acid  which  is  soluble  in  water,  and 
from  which  acids  do  not  precipitate  the  uric  acid,  this  compound 
has  been  introduced  as  a  therapeutic  agent.  Rosenfeld,^  for 
example,  obtained  good  clinical  results  from  urea;  others, 
Neumayer,''  for  example,  poor  results.  We  have  already  seen  that 
His  *  and  Klemperer "  proved  Riidel's  statement  to  be  erroneous. 

His  ^°  showed  that  in  the  creatinin  urate  of  Klemperer,''  which 
at  first  was  thought  to  be  a  non-electrolyte,  creatin  merely  acts 
like  any  other  alkali. 

Urotropin     (hexamethjdentetramine)     was    introduced    as    a 

1  W.  Herringham  and  E.  Groves.  On  the  Secretion  of  Uric  Acid,  Urea,  and  Ammonia. 
.Journ.  of  Physiol.,  12,  478  (1891). 

2  Schreiber  und  Waldvogel.  Beitrage  zur  Kenntniss  der  Harnsaureausscheidung  unter 
physiologischen  und  pathologischen  Verhaltnisse.  Arch,  fur  exp.  Path.  u.  Pharmak.,  42, 
69  (1899). 

3  Schreiber  und  Zaudy.  Zur  Wirkimg  der  Salicylpraparate  insbesondere  auf  die  Harn- 
saure  und  die  Leukocyten.     Deutsche  Arch,  fiir  klin.  Medizin,  62,  242  (1899). 

^  J.  Strauss.  Ueber  die  Einwirkung  des  kohlensauren  Kalkes  auf  den  menschhchen 
Stoffwechsel,  ein  Beitrag  zur  Therapie  der  harnsauren  Nierenconcrementen  nebst  Bemer- 
kungen  iiber  Alloxurkorperausscheidung.     Zeitschr.  flir  klin.  Medizin,  31,  493  (1896). 

5  Riidel.  Zur  Kenntniss  der  Losungsbedingungen  der  Harnsaure  in  Harn.  Arch,  fiir 
exp.  Path.  u.  Pharmak.,  30,  469  (1892). 

^  G.  Rosenfeld.  Zur  Diagnose  und  Therapie  der  Uratdiathese.  Centralblatt  fiir  innere 
Medizin,  16,  673  (1895). 

^  H.  Neumayer.  Ueber  die  Therapie  der  harnsauren  Diathese.  Verhandl.  des 
aerztlicher  verein  in  Miinchen,  9  Marz,  1898.  Deutsche  med.  Wochenschrift,  24,  vereins 
Beilage,  60  (1898). 

^W.  His.  Physikalisch-chemische  Untersuchungen  iiber  das  Verhalten  der  Harnsaure 
und  ihrer  Salze  in  Losungen.  Verhandl.  der  18t  Kongr.  fiir  innere  Med.,  Wiesbaden,  425 
(1900). 

^  G.  Klemperer.  Harnsaure  Kreatinin  eine  wasserloslich  Harnsaureverbindungen. 
Fortschritte  Med.,  19,  328. 

1"  W.  His.  Die  Harnsaureablagerungen  des  Korpers  und  die  Mittel  zu  ihrer  Liisung. 
Therapie  der  Gegenwart,  Neue  Folge,  3,  434  (1901). 


234      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

therapeutic  agent  by  Nicolaier.^  It  was  found  to  decompose  in 
the  body  and  appear  in  the  urine,  in  part,  at  least,  as  formalde- 
hyde by  Citron,^  Ortowski,^  Cammidge,^  and  His.^  Weber,  Pott, 
and  Tollens  **  found  that  formaldehyde  and  uric  acid  unite  to 
form  a  compound  which  is  not  a  salt.  Lobisch  ^  confirmed  this 
discovery,  and  attributed  the  action  of  urotropin  to  the  breaking 
up  of  this  com.pound  into  formaldehyde.  His  ^  came  to  the  same 
conclusion,  and  found  further  that  the  compound  of  formaldehyde 
is  not  a  salt.  The  uric  acid  is  not  precipitated  from  a  solution 
of  this  compound  by  acids. 

Nicolaier,*  Tanago,''  Ortowski,^"  and  Levison^^  found  that  the 
urine  of  patients  to  whom  urotropin  had  been  administered  has 
the  power  of  dissolving  uric  acid.  These  authors,  and  also 
Lobisch,''  have  found  this  drug  clinically  good  in  cases  of  uric 
acid  stones  and  gravel.  Tunicliffe  and  Rosenheim  ^^  found  that 
the  addition  of  urotropin  itself  to  a  urine  increases  slightly  the 
solvent  power  of  the  urine  for  uric  acid.  According  to  Rosenfeld 
and  Orgler,^^  urotropin  does  not  always  make  a  urine  a  better 

1  A  Nicolaier.  Ueber  die  therapeutische  Verwendung  des  Urotropin  (Hexamethyl- 
entetramine).     Deutsche  med.  Wochenschrift,  21,  541   (1895). 

2  A.  Citron.  Administration  of  Urotropine  and  Its  Effects  upon  the  Urine.  The 
Therapist,  8,  115  (1896),  also 

Ihid.  Monatsber.  iiber  die  Gesammtleistungen  auf  d.  Gebiete  d.  Krankh.  d.  Harn- 
und  Sexualorgane,  III,  2  (1898). 

SW.  Ortowski.  Ueber  die  bactericiden  Eigenschaften  des  Urotropin  und  seine  An- 
wendung  bei  Cystitis.     Petersbourg  (1899). 

^  P.   Cammidge.     Urotropine  as  a  Urinary  Antiseptic.     Lancet  (1901),    1,    174. 

5  W.  His.  Die  Harnsaureblagerungen  des  Korpers  und  die  Mittel  zu  ihrer  Losung. 
Vortrag.  auf  der  Versamml.  deutsch.  Naturforscher  und  Aerzte  in  Hamburg,  25  Sept. 
1901.     Therapie  der  Gegenwart,  Neue  Folge,  3,  434  (1901). 

6  K.  Weber,  R.  Pott,  und  B.  Tollens.  Ueber  Verbindungen  von  Fromaldehyde  und 
Harnsaure.     Ber.  der  Dtsch.  chem.  Gesell.,  30,  2514  (1897),  also 

K.  Weber  und  B.  Tollens.  Ueber  die  Einwirkung  von  Formaldehyde  auf  Harnsaure. 
Liebig's  Ann.,  299,  340   (1898). 

^  W.  Lobisch.  Ein  Fall  von  Pyelitis  calculosa  urica  behandelt  mit  Urotropin.  Wien. 
klin.  Wochenschrift,  10,  304  (1897). 

^  A.  Nicolaier.  Experimentelle  und  Klinisches  iiber  Urotropin.  Zeitschr.  fur  klin. 
Med.,  38,  356  (1899). 

'  M.  Tanago.  Pharmacologische  Behandlung  der  harnsauren  Diathese  und  besonders 
der  Lithiasis  urica.     El  Siglo  Medico,  2270-1,  June  27  and  July  4,  1897. 

'"  W.  Ortowski.  Vergleichende  L^ntersuchungen  iiber  Urotropin,  Piperazin,  Lysidin, 
Uricedin,  und  Natron  bicarbonicum  bei  der  harnsauren  Diathese.  Zeitschr.  ftir  klin. 
Med.,  40,  331  (1900). 

1'  F.  Levison.  Werthvergleichung  der  Heilmittel  der  harnsauren  Diathese.  Ugeskrift 
for  Laeger,  (1896-97). 

12  F.  Tunicliffe  and  O.  Rosenheim.  Piperidine  as  a  Uric  Acid  Solvent,  a  comparative 
study.     Lancet  (1898),  2,  198. 

"  Rosenfeld  und  Orgler.  Zur  Behandlung  der  harnsauren  Diathese.  Centralblatt  fi'ir 
innere  Medizin,  17,  42  (1896). 


Physiology  235 

solvent  for  uric  acid.  More  experiments  are  needed  before  -sve 
can  conclude  that  urotropin  is  a  valuable  therapeutic  agent  in 
cases  of  uric  acid  calculi.  It  may  be  mentioned  incidentally 
that  the  toxic  effects  attributed  by  some  writers  to  this  drug 
in  certain  cases  have  been  found  by  Coleman  ^  to  occur  but 
rarely. 

It  will  be  remembered  (see  p.  69)  that  Kossel,  Minkowski,  and 
Goto  found  that  nucleic  acid,  and  Kossel  and  Goto  that  the  so- 
called  thymic  acid  have  the  power  of  uniting  with  uric  acid  to 
form  compounds  which  are  not  salts,  and  therefore  not  decom- 
posed by  acid.  These  authors  recommended  that  nucleic  and 
"  thymic  "  acid  might  be  tried  as  therapeutic  agents.  Nucleic 
acid  has  the  disadvantage  of  containing  purin  bodies,  which  in- 
crease the  excretion  of  uric  acid,  and  it  seems  to  be  impossible 
to  get  a  "  thymic  "  acid  free  from  purin  bases.  Besides,  although 
these  acids  may  dissolve  uric  acid  in  a  test  tube,  they  will  decom- 
pose in  the  body  and  therefore  not  reach  the  urine  in  such  a  form 
as  to  be  of  any  value. 

There  are,  then,  no  substances  which  have  been  shown  to  have 
any  effect  on  the  solubility  of  uric  acid  in  the  urine. 

The  Effect  of  Drugs  on  the  Solubility  of  Uric  Acid 
in  the  Blood 

According  to  the  belief  of  Haig  "  and  many  others,  when  the 
blood  becomes  overcharged  with  uric  acid,  either  on  account  of 
the  formation  of  large  quantities  of  uric  acid,  or  on  account  of 
decreased  alkalinity,  the  uric  acid  deposits  in  some  part  of  the 
body.  If  the  deposit  occurs  in  the  joints,  we  get  rheumatism  or 
gout.  To  treat  this  condition,  Haig  decreases  the  foods  which 
are  believed  to  give  excessive  uric  acid,  and  administers  alkalies 
to  increase  the  alkalinity  of  the  blood  in  order  to  keep  uric  acid 
in  solution  and  to  dissolve  concretions  already  formed.  He 
says,^  "  We  have  only  now  to  suppose  what  I  expect  no  one  will 
dispute,  that  a  dose  of  acid  will  diminish  the  alkalescence  of  the 
blood  and  tissue  fluids,  and  also  of  the  liver  and  spleen,  and  that 

^  W.  Coleman.  The  Toxic  Actions  of  Urotropin,. with  Report  of  a  Case  of  Hematuria 
and  Hemoglobinurea,  following  a  Dose  of  Seven  and  One-Half  Grains.  Med.  News,  S3, 
393  (1903). 

^  A.  Haig.     Uric  Acid  as  a  Factor  in  the  Causation  of  Disease.    London,  1896. 

^  Ibid.  Variations  in  the  Excretion  of  Uric  Acid  produced  by  Administration  of  .\cids 
and  Alkalies.     Journ.  of  Physiol.,  8,  211  (1887). 


236      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

a  dose  of  alkali  will  produce  the  reverse  effect,  to  see  why  and 
how  they  may  alter  the  excretion  of  uric  acid  in  the  way  I  have 
shown  that  they  do."  The  view,  first  suggested  by  Wollaston,^ 
that  by  the  administration  of  alkalies  we  can  dissolve  concre- 
tions of  sodium  acid  urate  in  the  body,  has  served  as  the  basis 
for  those  theories  of  Haig  which  are  so  widely  adopted  and  which 
attribute  so  many  diseases  to  uric  acid.  This  view  is  certainly 
open  to  dispute. 

Hober  ^  was  the  first  to  determine  the  alkalinity  of  the  blood 
expressed  in  terms  of  the  concentration  of  the  hydroxyl  ions. 
He  found  it  to  vary  from  0.22  X  10"^  to  0.9  X  10"^ 

More  recent  determinations  by  Hober  ^  give  much  lower  figures, 
viz.:  0.7  X  10-^  to  2.0  X  10~^  Farkas,^  who  has  likewise 
determined  the  concentration  of  the  hydroxyl  ions  in  the  blood, 
obtained  about  the  same  results,  viz.:  1.  X  10"''  to  3.  X  10~''. 
This  author  showed  that  Hober's  higher  results  are  due  to  a 
slight  error  in  his  method.^  Fraenckel  ^  obtained  still  lower 
values. 

All  other  determinations  have  been  made  by  titration  methods 
or  by  other  methods  which  give  the  "  potential  "  alkalinity, 
that  is,  the  concentration  of  the  hydroxyl  ions  available  from 
the  basic  salts,  such  as  alkaline  sodium  phosphate  and  sodium 
carbonate.  The  figures  indicate  that  the  alkalinity  of  the  blood 
is  very  low,  comparable  in  part  with  the  alkalinity  of  very  pure 
water  which  has  hydroxyl  ions  to  the  extent  of  about  .8  X  10~^ 
gram  molecules  per  liter.  The  sulphuric  acid  formed  by  the 
oxidation  of  but  a  fifth  of  a  milligram  of  sulphur  would  be  enough 
to  neutralize  completely  the  alkalinity  of  the  whole  five  liters  of 
blood.  Yet,  in  spite  of  the  fact  that  considerable  quantities  of 
acid  are  continuously  being  formed  by  the  oxidation  of  the  sul- 
phur and  phosphorus  of  the  body  and  food,  and  in  other  ways, 
and  introduced  into  the  blood,  the  blood  is  always  alkaline. 
This  indicates  that  there  must  be  some  regulating  power  which 

1  Wollaston.     On  Gouty  and  Urinary  Concrements.     Phil.  Transactions  (1797),  388. 

2  R.  Hober.  Ueber  die  Hydroxylionen  des  Blutes.  Pfliiger's  Archiv,  81,  522 
(1900). 

^Ibid.     Pfliiger's  Archiv,  99,  572    (1903). 

■*  G.  Farkas.  Ueber  die  Konzentration  der  Hydroxylionen  im  Blutserum.  Pfliiger's 
Archiv,  98,  551  (1903). 

6  Ibid.     Arch,  fiir  Physiol.  (1903),  Suppl.,  517. 

*  P.  Fraenckel.  Eine  neue  Methode  zur  Bestimmung  der  Reaktion  des  Blutes.  Pfliiger's 
Archiv,  96.  601  (1903). 


Physiology  237 

maintains  the  alkalinity  of  the  blood. ^  Since,  then,  the  intro- 
duction of  large  quantities  of  acid  from  within  does  not  normally 
have  any  influence  on  the  alkalinity  of  the  blood,  it  seems  hardly 
probable  that  we  can  directly  influence  the  alkalinity  of  the  blood 
in  physiological  cases  by  the  introduction  of  small  quantities  of 
acids  or  alkalies  from  without.  Freudberg  ^  has  found  that  the 
administration  of  from  4  to  8  grams  HCl  per  day  does  not  influ- 
ence the  alkalinity,  of  the  blood  as  determined  by  even  titration 
methods,  and  Magnus-Levy  ^  could  not  find  that  the  administra- 
tion of  18  grams  HCl  or  40  grams  NaHCOg  has  any  influence. 

The  next  question  is  whether  the  addition  of  alkali  or  acid 
directly  to  blood  serum  would  affect  its  power  of  dissolving  uric 
acid.  A  precipitation  of  uric  acid  from  blood  will  occur  only  when 
the  concentration  of  the  H  ions  and  the  negative  uric  acid  ions, 
u,  is  such  that  the  value  Cn  X  CtJ  is  greater  than  206  X  10~^-. 
A  precipitation  of  sodium  acid  urate  will  occur  only  when  the 
concentration  of  Na  and  iJ  are  such  that  the  value  for  k  in  the 
equation  CNa  X  Cu  =  k  is  exceeded.  On  addition  of  acid  to  a 
blood  serum,  the  H  ions  from  the  acid  will  unite  with  the  OH  ions 
in  the  serum  to  form  undissociated  HOH.  On  neutralization  of 
the  "  actual  "  OH  ions,  new  OH  ions  are  set  free  to  reestablish 
equilibrium.  This  is  shown  by  the  fact  that  the  titration  methods 
give  blood  such  a  high  alkalinity  compared  with  the  electro- 
chemical methods.  The  addition  of  acid,  then,  does  not  affect 
the  values  Ch,  Cu,  or  CNa  until  enough  acid  is  added  to  make  the 
blood  practically  neutral.  We  cannot,  of  course,  reach  this 
point  with  the  blood  in  the  living  body. 

1  Among  the  different  conditions  of  equilibrium  in  the  blood  we  have 

^"  ^  ^"""^  =  k2  and  Ch  X  Cqh  =  k,.     Then  ^^  =  K  =         ^"^f^ . 

CH2PO4  ^1  t^OH  X  CH2PO4 

Therefore,  when  Coh  decreases  by  addition  of  acid,  Chpo4  ™ust  decrease  or  CH9PO4 
increase  to  maintain  equilibrium.  The  reaction:  HP0"4  +  HOH  =  H^POU  +  OH', 
whereby  HPO4  decreases  and  H2PO4  increases,  would  reestablish  equilibrium.  In  the  same 
way,  from  the  equation 

k3  =  K  =  ^"^°«       ,  where  kg^  Ch  X  Chcos 

ki  Coh  X  CH2CO3  CH2CO3 

we  can  see  that  the  reaction  HCO'3  +  HOH  =  H2CO3  +  OH'  would  also  re-establish  equi- 
librium after  disappearance  of  OH  ions.  In  either  case  the  potential  hydroxyl  ions  come 
directly  from  the  water,  but  are  due  to  the  presence  of  salts  of  strong  acids  and  weak  bases. 
R.  Hober.  Die  Aciditat  des  Harns  vom  Standpunkt  der  lonenlehre.  Beitrage  z. 
chem.  Physiol,  u.  Path.,  3,  525  (1903). 

2  H.  Freudberg.  Ueber  den  Einfluss  von  Sauren  und  Alkalien  auf  die  Alkalescenz  des 
Blutes  und  die  Reaktion  des  Harnes.     Virchow's  Archiv,  125,  566  (1891). 

3  A.  Magnus-Levy.  Harnsauregehalt  und  Alkalescenz  des  Blutes  in  der  Gicht.  Ver- 
handl.  des  16t  Kongr.  fiir  innere  Med.,  266  (1898). 


238      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

The  concretions  in  case  of  gout  are  of  sodium  acid  urate,  so 
that  it  is  only  the  solubility  of  sodium  acid  urate  in  the  blood 
with  which  we  have  to  deal.  Increasing  Coh  by  making  the 
blood  more  alkaline  does  not  change  the  values  for  CNa  or  Ctj. 
We  cannot,  therefore,  increase  the  dissolving  power  of  the  blood 
for  sodium  acid  urate  even  if  we  do  increase  the  alkalinity  of 
the  blood. 

The  experimental  proof  that  addition  of  acid  does  not  precipi- 
tate uric  acid  or  urate  from  a  blood  serum  was  given  by  Luff.^ 
This  author  found  that  addition  of  enough  HCl  or  tartaric  acid 
to  neutralize  one  half,  one  fourth,  or  even  three  fourths  the 
alkalinity  of  the  blood  does  not  bring  about  a  precipitation  of 
uric  acid  or  urate  from  a  concentrated  solution  of  uric  acid  in 
blood  serum. 

The  experiments  of  Tunicliffe  and  Rosenheim  ^  showing  that 
the  addition  of  organic  bases  to  blood  serum  increases  its  solvent 
power  for  uric  acid  do  not  come  into  consideration,  since  it  is 
sodium  acid  urate  and  not  uric  acid  that  we  have  to  deal  with  in 
gout. 

Klemperer  ^  has  shown  that  the  alkalinity  of  the  blood  (deter- 
mined by  titration)  is  not  decreased  in  gout,  and,  further,  that 
the  blood  is  not  saturated  with  uric  acid.  It  can,  in  fact,  dissolve 
about  as  much  uric  acid  as  normal  blood,  so  that  there  is  no  need 
of  making  the  blood  more  alkaline  or  a  better  solvent  for  uric 
acid. 

To  sum  up,  then,  first,  there  is  no  reason  to  believe  that  we 
can  directly  increase  or  decrease  the  alkalinity  of  the  blood  by 
the  administration  of  alkalies  or  acid;  second,  a  change  in  the 
alkalinity  of  the  blood  will  not  affect  the  solubility  of  sodium  acid 
urate  in  it;  third,  the  "  potential  "  alkalinity  of  the  blood  and 
its  power  of  dissolving  sodium  acid  urate  are  not  decreased  in 
gout,  so  that  there  is  no  basis  for  trying  to  bring  the  alkalinity 
back  to  a  normal  condition  or  for  attempts  to  make  the  blood  a 
better  solvent  for  uric  acid. 

1  A.  Luff.  (Goulstonian  Lectures.)  The  Chemistry  and  Pathology  of  Gout  Lancet 
(1897),  1,  857,  942,  1069. 

2  F.  Tunicliffe  and  D.  Rosenheim.  Piperidine  as  a  Uric  Acid  Solvent,  a  comparative 
study.     Lancet  (1898),  2,  198. 

3  G.  Klemperer.  Zur  Pathologic  und  Therapie  der  Gicht.  Deutsche  med.  Woehen- 
schrift,  21,  665  (1895). 


Physiology  239 

EFFECTS  OF  ALKALIES  ON   URIC  ACID  CONCRETIONS  IN 

BIRDS 

Certain  authors  have  performed  experiments  on  birds  in  the 
endeavor  to  show  that  the  administration  of  alkahes  increases 
the  dissolving  power  of  the  blood  and  fluids  of  the  body  for  uric 
acid.  Ebstein  ^  and  others  had  shown  that  the  administration 
of  potassium  chromate  to  hens  and  doves  brought_about  the 
formation  of  concretions  of  uric  acid  in  the  kidneys  similar  to 
those  formed  when  the  ureters  are  tied.  Kossa  ^  found  that 
aloin,  sublimate,  oxalic  acid,  carbolic  acid,  aceton,  and  other 
kidney  poisons  bring  about  the  same  result.  This  author  attrib- 
uted the  formation  of  the  concretions  to  slow  destruction  of 
the  kidney  functions.  Similar  concretions  are  found  in  hens 
when  they  are  fed  on  meat  for  a  long  period.  Biesenthal  ^  found 
that  the  administration  of  potassium  chromate  does  not  bring 
about  uric  acid  concretions  in  hens  if  piperazin  is  given  at  the 
same  time.  Richter  *  performed  two  series  of  experiments  on 
birds.  In  one  series,  potassium  chromate  alone  was  adminis- 
tered. In  the  other  series  both  sidonal  (quinate  of  piperazin) 
and  potassium  chromate  were  given.  Concretions  of  uric  acid 
occurred  in  the  kidneys  of  the  birds  used  in  the  first  series.  No 
concretions  occurred  in  the  birds  used  in  the  second  series. 
According  to  Hoffmann,^  no  concretions  of  uric  acid  occur  in 
hens  after  meat-eating  if  certain  alkaline  spring  waters  are  ad- 
ministered at  the  same  time. 

Some  authors  have  concluded  that  these  experiments  indicate 
that  alkalies  are  good  therapeutic  agents  in  gout,  and  that  the 
good  action  can  be  attributed  to  a  solution  of  the  uric  acid  in  the 
joints.  Such  conclusions  are  not  warranted.  Uric  acid  holds 
a  different  position  in  the  metabolism  of  birds  from  that  which 

1  Ebstein.     Die  Natur  und  Behandlung  der  Gicht.     Wiesbaden  (1882'!. 

2  J.  Kossa.  Ktinstliche  Erzeugung  der  Gicht  durch  Gifte.  Arch,  internat.  de  Pharm- 
acodynamie,  5,  97  (1898) ;  Maly's  Jahresb.  fiber  die  Fortschritte  der  Thierohemie,  28,  678 
(1898). 

3  P.  Biesenthal.  Wirkung  des  Piperazin  bei  kunstlich  erzeugten  Harnsaureablager- 
ungen  im  thierischen  Organismus.  Verhandl.  der  Berliner  med.  Gesell.,  July  12,  1893; 
Berl.  klin.  Wochenschrift,  30,  805  (1893),  also 

Ihid.  Ueber  den  Einfluss  des  Piperazin  auf  die  harnsauren  Diathese.  Virchow's 
Archiv,  137,  51  (1894). 

•t  P.  Richter.  Ueber  die  experimentelle  Priifung  sogennanter  "Gichtmittel"  im  Allgem- 
einen  und  iiber  die  Chinasaure  und  das  chinasaure  Piperazin  im  Besonderer.  Charity 
Annalen,  25,   197  (1900). 

5  P.  Hoffmann.  Beitrage  zur  Kenntniss  der  Kronenquelle  zu  Salzbrunn  in  Schlesien 
Breslau  (1901). 


240      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

it  holds  in  the  metabolism  of  mammals.  We  cannot  consider 
the  conditions  brought  about  in  birds  by  potassium  chromate 
and  other  kidney  poisons  analogous  to  real  gout.  According  to 
Biesenthal/  the  chromate  causes  destruction  of  the  parenchyma 
of  the  kidney.  We  have  then  a  retention  of  the  end  product  of 
nitrogenous  metabolism  due  to  the  destruction  of  the  kidney. 
This  is  a  condition  more  nearly  approaching  uremia  in  man.  If 
piperazin  prevents  the  formation  of  the  concretions,  it  is  for 
some  unknown  reason,  and  it  is  undoubtedly  not  due  to  any 
effect  on  the  dissolving  power  of  the  blood  for  uric  acid. 

It  is  even  very  doubtful  if  the  administration  of  alkalies  does 
prevent  the  formation  of  concretions  in  birds  after  injection  of 
chromate.  According  to  Meisls,  although  piperazin  prevents 
the  concretions,  neither  LiCOg^  nor  uricedin^  prevents  them. 
Aujeszky  and  Donogany,*  too,  found  that  uricedin  does  not  pre- 
vent the  formation  of  concretions  after  chromatic  injections. 
According  to  Ortowski,^  neither  urotropin,  lysidin,  piperazin, 
NaHCOg  nor  uricedin  has  any  effect  in  preventing  the  concre- 
tions.    According  to   Kossa,"  piperazin  makes   them  worse. 

The  Effect  of  Drugs  on  the  Size  of  the  Uric  Acid  Excretion 

The  effect  on  the  excretion  of  uric  acid  of  those  drugs  found 
clinically  good  in  gout  has  been  studied  by  numerous  physiolo- 
gists. An  increased  excretion  of  uric  acid  after  a  drug  may  be 
due  to  an  increase  in  the  amount  either  of  the  endogenous  or 
the  exogenous  uric  acid  formed  from  nucleins,  or  to  a  decrease 
in  the  amount  of  uric  acid  oxidized,  or,  possibly,  to  a  formation  of 
uric  acid  from  some  other  source.  A  decreased  excretion  of  uric 
acid  may  be  due,  on  the  other  hand,  to  a  decrease  in  the  forma- 

1  p.  Biesenthal.  Wirkungen  des  Piperazin  bei  kiinstlich  erzeugten  Harnsaureablager- 
iingen  im  thieiischen  Organismus.  Verhandl.  der  Berliner  med.  Gesell.,  .July  12,  1893; 
Berl.  klin.  Wochenschrift,  30,  805  (1893). 

^  W.  Meisls.  Experimente  mit  Piperazin  und  anderen  uratlosenden  Mitteln;  Un- 
garisches  Arch,  fiir  Med.,  1,  364  (1893);  Maly's  Jahresb  tiber  die  Fortsohritte  der  Thier- 
chemie,  23,  582  (1893). 

^  Ibid.       Einige  Versuche    mit    Uricedin.     Pester   med.-chir.    Presse,    30,     684    (1894). 

*  A.  Aujeszky  und  Z.  Donogany.  Ueber  die  uratlosende  Wirkung  des  Uricedin.  Pester 
med.-chir.  Presse,  30,  681  (1894). 

5  W.  Ortowski.  Vergleichende  Untersuchungen  tiber  Urotropin,  Piperazin,  Lysidin, 
Urecidin,  und  Natron  bicarbonicum  bei  der  harnsauren  Diathese.  Zeitschr.  ftir  klin. 
Medizin,  40,  331  (1900). 

'^  J.  von  Kossa.  Klinstliche  Erzeugung  der  Gicht  durch  Gifte.  Arch,  internat.  de 
Pharmacodynamie,  5,  97  (1898) ;  and  Maly's  Jahresb.  tiber  die  Fortschritte  der  Thierchemie, 
28,  678  (1898). 


Physiology  241 

tion  of  uric  acid,  or  to  the  fact  that  a  larger  amount  is  "oxidized 
than  normally.  So  long  as  we  do  not  know  the  significance  of 
decreased  and  increased  excretion  of  uric  acid  after  drugs,  and 
in  what  the  abnormalities  in  the  metabolism  of  uric  acid  consist 
in  gout,  there  is  no  reason  for  giving  a  drug  in  gout  because  of  its 
effect  on  the  amount  of  uric  acid  in  the  urine. 

If,  on  the  other  hand,  alkalies,  for  example,  are  found  clini- 
cally good  in  gout,  the  good  effect  cannot  be  attributed  to  the 
fact  that  they  make  the  blood  a  better  solvent  for  uric  acid,  that 
they  cause  an  "  alkaline  tide  "  that  "  sweeps  out  "  the  uric  acid, 
to  use  Haig's  terms.  Neither  can  we  say  that  the  alkalies  decrease 
the  production  or  hasten  the  oxidation  of  uric  acid.  The  good 
action,  if  there  is  any,  must  be  attributed  to  some  other  influence 
on  the  general  metabolism. 

ALKALIES 

Gorsky  ^  found  a  slight  increase  in  the  excretion  of  uric  acid 
after  LiCOg,  and  Zagari  and  Pace  ^  after  other  alkalies.  Salkow- 
ski  ^  observed  increased  excretion  of  uric  acid  in  dogs  after  ad- 
ministration of  sodium  acetate,  which  oxidizes  to  carbonate. 
Axenfeld,^  who  used  the  Hay  craft  method  for  the  determination 
of  uric  acid,  observed  sometimes  a  very  slightly  increased  excre- 
tion of  uric  acid  after  ammonium  tartrate.  According  to  Dapper,^ 
Vogel,**  and  Bain,^  piperazin  causes  a  slight  increase  in  the  excre- 
tion of  uric  acid,  and  according  to  Bain,^  lysidin  has  the  same 
effect.  According  to  Gilardoni,^  alkaline  water  increases  the 
excretion  of  uric  acid. 

'  G.  Gorsky.  Ueber  den  Einfluss  des  Lithiumcarbonate  auf  den  Stickstoffwechsel  bei 
Gesunden.     Centralblatt  fiir  der  med.  Wissen.,  28,  27  (1890). 

2  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  pato- 
genesi  e  all'  indirizzo  terapeutico.  Napoli,  1897.  Centralblatt  fur  innere  Medizin,  190, 
816  (1898). 

^  E.  Salkowski.  Ueber  die  Grosse  der  Harnsaureausscheidung  und  den  Einfluss  der 
Alkalien  auf  dieselbe.  Virchow's  Archiv,  117,  590  (1889),  and  Spilker.  Ueber  den  Ein- 
fluss der  Alkalien  auf  den  Stoffwechsel  mit  besonderer  Beriicksichtigung  der  Harnsaure. 
Inaug.  Dissert.,   Berl.,   1890. 

*  D.  Axenfeld.  Intorno  alia  transformazione  dei  sali  di  anxmonio  in  urea  nell'  organ- 
ismo.  Annali  di  chimica  e  di  farmacologia,  p.  172  (1888),  and  Maly's  Jahresb.  iiber  di. 
Fortschritte  der  Thierchemie,  18,  122  (1888). 

5  K.  Dapper.  Ueber  Harnsaureausscheidung  beim  gesunden  Menschen  unter  verscheid- 
enen  Ernahrungsverhaltnissen.     Berl.  klin.  Wochenschrift,  30,  617  (1893). 

^  L.  Vogel.     In  von  Noorden's  Beitrage  zur  Ijehre  von  Stoffwechsel.     Berl.  (1894),  2,  113. 

^  W.  Bain.  The  Influence  of  Some  Modern  Drugs  on  Metabolism  in  Gout.  Brit.  Med. 
Journ.  (1903),  1,  243. 

8  A.  Gilardoni.  Beitrag  iiber  den  Einfluss  des  alkalischen  mineralwassers  auf  Stickstoff- 
und  Harnsaureausscheidung.     Therap.  Monatsh.,   18,  69  (1904). 


242      The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

On  the  other  hand,  Laveran  and  Millon  ^  found  that  sodium 
potassium  tartrate,  which  oxidizes  in  the  body  to  carbonate, 
decreases  the  excretion  of  uric  acid.  Moss  ^  found  that  sodium 
acetate  likewise  decreases  the  excretion  of  uric  acid.  Laveran  and 
Millon  and  Moss  used  the  inaccurate  Heinz  method  for  the  deter- 
mination of  uric  acid.  Stadelmann  ^  found  that  alkalies  cause  a 
slight  decrease  in  the  excretion  of  uric  acid.  Munch  *  found  the 
excretion  of  uric  acid  decreased  after  doses  of  three  or  four  gram.s 
NajCOg  per  day.  According  to  Laquer,^  the  excretion  of  uric 
acid  is  decreased  after  drinking  Ems  spring  water,  which  contains 
the  carbonates  of  both  sodium  and  potassium. 

Lo  Monaco  ^  found  that  the  excretion  of  uric  acid  is  decreased 
after  drinking  water  containing  CaH2(C03)2.  According  to 
Aujeszky  and  Donogany,'''  uricedin  causes  a  decrease  in  the  ex- 
cretion of  uric  acid,  but  their  results  do  not  seem  to  indicate  that 
the  drug  has  any  effect  in  this  direction.  His  ^  observed  a  very 
slightly  decreased  excretion  of  uric  acid  after  LiCOg. 

Clar  ^  found  first  a  slight  increase  and  then  a  decrease  in  the 
excretion  of  uric  acid  after  NaoCOg.  According  to  Umber, ^^ 
NaHCOg  increases  the  excretion  of  purin  bases.  According  to 
Determeyer  and  Biittner,"  certain  alkaline  spring  waters  (Ober- 
brunnen)  cause  decreased  excretion  of  uric  acid  in  health,  but 
increased  uric  acid  in  the  uric  acid  diathesis. 

1  Laveran  et  Millon.  M^moire  sur  le  passage  de  quelques  medicaments  dans  I'^conomie 
animale,  et  sur  les  modifications  qu'ils  y  subissent.  Annales  de  chimie  et  de  physique, 
3  ser.,  XII,  135  (1844). 

-Moss.  On  the  Action  of  Potash,  Soda,  Lithia,  Lead,  Opium,  and  Colchicum  on  the 
Urine.     Amer.  Journ.  of  Med.  Sciences,  XLI,  384  (1861). 

3  E.  Stadelmann.  Ueber  den  Einfluss  der  Alkalien  auf  den  menschlichen  StofEwechsel. 
Verhandl.  des  9t  Kongr.  fiir  innere  Medizin,  Wiesbaden,  p.  381  (1890). 

^  Munch.  Wirkung  des  kohlensaures  Natrons  auf  den  menschlichen  Korper,  insbeson- 
dere  den  Stoffwechsel.     Arch.   d.   wissenschaftisch.   Heilk.,   6,   369. 

•'  W.  Laquer.  Der  Einfluss  der  Emser  Quellen  auf  die  Harnsaureausscheidung  des 
Menschen.     Berl.  klin.  Wochenschrift,   40,   586   (1903). 

^  D.  Lo  Monaco.  Gli  effecti  della  acque  alcaline  sul  consume  azodato  e  sulla  forma- 
zione  dell'  acido  urico.     Policlinico,  3,  346  (1896) ;  Schmidt's  Jahrb.,  253,  124  (1897). 

'  A.  Aujeszky  und  Z.  Donogany.  Ueber  die  uratlosende  Wirkung  des  Uricedin.  Pester 
med.-chir.  Presse,  30,  681  (1894).' 

8  W.  His.  Die  Ausscheidung  von  Harnsaure  im  Urin  der  Gichtkranken  mit  besonderer 
Beriicksichtigung  der  Anfallszeiten  und  Behandlungsmethoden.  Deutsche  Arch,  fiir 
klin.  Medizin,  65,  156  (1900);    also 

Ibid.     Untersuchungen  an  Gichtkranken.     Wien.  med.  Blatter,   19,  291   (1896). 

^  C.  Clar.  Ueber  den  Einfluss  des  kohlensauren  Natrons  aud  die  Stickstoffausscheidung 
beim  Menschen.     Centralblatt  fiir  die  med.  Wis.sen.,  26,  466  (1888). 

'"  F.  Umber.  Ueber  den  Einfluss  nucleinhaltiger  Nahrung  auf  die  Ilarnsaurebildung. 
Zeitschr.  fiir  klin.  Med.,  29,  174  (1896). 

1'  Determeyer  und  Btittner.  Zur  Therapie  der  harnsauren  Diathese.  Deutsche  med. 
Wochenschrift,  27,  336  (1901). 


Physiology  243 

The  bulk  of  the  evidence  seems  to  indicate  that  the  alkalies 
neither  decrease  nor  increase  the  excretion  of  uric  acid.  Thus, 
neither  Spilker/  Keniptner,^  Laquer,^  nor  Rosenfeld  *  could 
observe  that  the  administraton  of  alkalies  has  any  effect  on  the 
excretion  of  uric  acid  in  man.  According  to  Severin,^  the  admin- 
istration of  from  two  to  four  grams  NajCO,,  per  day  does  not 
affect  the  quantity  of  uric  acid  excreted.  Herrmann  "  could  not 
observe  that  sodium  or  potassium  tartrate  which  oxidize  to  car- 
bonates, nor  Weiss  ^  that  the  potassium  salts  of  other  plant  acids 
have  any  effect  on  the  excretion  of  uric  acid,  and  Bain  could  not 
find  that  piperazin  tartrate  has  any  effect.  After  the  adminis- 
tration of  an  alkaline  spring  water  (Tarasperwasser,  Luciusquelle), 
containing  the  bicarbonates  of  sodium,  potassium,  and  magnesium, 
Leva  ^  found  that  the  excretion  of  uric  acid  is  not  changed,  and 
after  Fachinger  and  Offenbacher  waters,  which  contain  NaHCOg, 
Schreiber  and  Zaudy  ^  found  that  the  excretion  of  uric  acid  is  not 
changed.  His  ^°  could  not  find  any  effect  on  the  excretion  of  uric 
acid  from  NaHCOg,  Fachinger  water,  lysidin,  piperazin,  or  uri- 
cedin.     Levison,"  Ebstein  and  Sprague,^^  Vogel,^^  and  Biesenthal 

1  E.  Spilker.  Ueber  den  Einfluss  der  Alkalien  auf  den  Stickstoffwechsel  mit  besonderer 
Beriicksichtigung  der  Harnsaure.     Inaug.  Dissert.,  Berlin,  1889. 

2  Kemptner.  Ueber  die  Stickstoff-  und  Harnsaureausscheidung  bei  Zufuhr  von 
kohlensauren  resp.  citronsauren  Natron.  From  Stadelmann.  Ueber  den  Einfluss  der  Alka- 
lien auf  den  menschlichen  Stoffwechsel.     Stuttgart,  1890. 

3  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  im  Harne  von 
Gesunden  und  Kranken.     Verhandl.  des  14t  Kongr.  fiir  innere  Medizin,  333  (1896). 

*  G.  Rosenfeld.  Grundzuge  der  Berhandlung  der  harnsauren  Diathese.  Verhandl. 
des  14t  Kongr.  fur  innere  Medizin,  318  (1896). 

5  Severin.  Ueber  die  Einwirkung  des  kohlensaures  Natrons  auf  den  Gehalt  des  Harns 
an  Harnsaure.     Inaug.  Dissert.  (1868),  Marburg. 

!>  A.  Herrmann.  Ueber  die  Abhangigkeit  der  Harnsaureausscheidung  von  Nahrungs- 
und  Genussmitteln  mit  Riicksicht  auf  die  Gicht.  Deutsche  Arch,  fiir  klin.  Medizin,  43, 
273  (1888). 

"  J.  Weiss.  Eine  neue  Methode  der  Behandlung  der  harnsauren  Diathese.  Berl.  kUn. 
Wochenschrift,  36,  297  (1899). 

*  J.  Leva.  Ueber  die  Einwirkung  des  Tarasperwassers  (Luciusquelle)  auf  den  Stoff- 
wechsel.    Berl.  klin.  Wochenschrift,  31,  260,  und  291  (1894). 

f"  Schreiber    und   Zaudy.     Zur   Wirkung   der    Offenbacher    Kaiser    Friedriohs- Quelle. 

Zeitschr.  fiir  diat  und  physikal.  Therapie,  2,  136  (1899). 

1°  W.  His.     Untersuchungen  an  Gichtkranken.    Wien.  med.  Blatter,  19,  291  (1896),  and 
Ihid.     Die   Ausscheidung   von   Harnsaure   im   Urin   der   Gichtkranken  mit  besonderer 

Beriicksichtung    der    Anfallszeiten    und   bestimmter    Behandlungsmethoden.       Deutsche 

Arch,  fiir  klin.  Medizin,  65,  156  (1900). 

11  C.  Levison.  Ueber  den  Einfluss  einiger  Medicamente  auf  Harnsaureausscheidung  und 
Leukocytenzahl.     Dissert.,   Bonn    (1897). 

12  W.  Ebstein  und  C.  Sprague.  Notiz,  betreffend  die  therapeutische  Anwendung  des 
Piperazin.     Berl.  klin.  Wochenschrift,  28,  341  (1891). 

_.!' Vogel.     Ueber    den    Stoffwechsel  bei    Gichtkranken.     Verhandl.    der    Berl.   physiol. 
Gesellsch.,  17  Feb.,  1893,  und  Du  Bois  Archiv,  377  (1893). 


244      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

and  Schmidt  ^  found  that  piperazin,  and  Klemperer  and  Ziesig  - 
that  lysidin  does  not  afifect  the  excretion  of  uric  acid.  Meisls  ^ 
showed  that  uricedin,  and  Strauss  *  that  CaCOg,  has  no  effect  on 
the  excretion  of  uric  acid. 

WATER  AND  NEUTRAL  SALT  SOLUTIONS 

The  drinking  of  large  quantities  of  water  does  not  seem  to  have 
any  effect  on  the  amount  of  uric  acid  excreted  in  man,  according 
to  Kusmanoff/  Schondorff,"  Hopkins  and  Hope/  Schreiber,*  and 
Gilardoni.^  Only  Genth/*'  who  used  an  inaccurate  method  of 
analysis,  and  who  found  decreased  uric  acid  after  water  drinking, 
observed  any  effect  of  water  drinking.  In  cases  of  heart  disease, 
the  amount  of  uric  acid  excreted  per  day  was  somewhat  depend- 
ent upon  the  quantity  of  urine  excreted  in  the  experiments  of 
Kobler "  and  Husches.^^  Unfortunately,  Kobler's  patient  was 
taking  digitalis  during  the  experiment.  Laquer  ^^  seemed  to  find 
a  relation  between  the  quantity  of  water  taken  and  the  amount  of 
purin  bases  excreted.  He  used,  however,  the  inaccurate  Kriiger- 
Wulff  method  of  determination.  Burian  and  Schur  ^^  found  that 
the  excretion  of  uric  acid  is  increased  in  dogs  by  diuresis. 

1  Biesenthal  und  Schmidt.  Piperazin  bei  Gicht  und  Steinleiden.  Berl.  klin.  Wochen- 
schrift,  28,  1231  und  1214  (1891). 

2  Klemperer  und  Ziesig.  Bericht  iiber  die  Behandlung  von  drei  Gichtkranken  mit 
Lysidin.     Klemperer's  Untersuchungen   (1896). 

3  W.  Meisls.     Einige  Versuche  mit  Uricedin.     Pester  med.-chir.  Presse,  30,  684  (1894). 
*  J.  Strauss.     Ueber  die  Einwirkung  des  kohlensauren  Kalkes  auf  den  menschlichen 

Sto£fwechseI,  ein  Beitrag  zur  Therapie  der  liarnsauren  Nierenconcrementen  nebst  Bemer- 
kungen  uber  Alloxurkorperausscheidung.     Zeitschr.  fur  klin.  Med.,  31,  493  (1896). 

5  A.  Kusmanoff.  Die  Ausscheidung  der  Harnsaure  bei  absoluter  Milchdiat.  Inaug. 
Dissert.,  Dorpat,  1885. 

6  B.  Schondorff.  Ueber  den  Einfluss  des  Wassertrinkens  auf  die  Ausscheidung  der 
Harnsaure.     Dissert.,  Bonn,  1890,  and  Pfliiger's  Archiv,  46,  529  (1890). 

'  F.  Hopkins  and  W.  Hope.  On  the  Relation  of  Uric  Acid  to  Diet.  Journ.  of  Physiol., 
23,  271  (1898). 

sSchreiber.     Ueber  die  Harnsaure,  38,  Stuttgart,  1899. 

9  A.  Gilardoni.  Beitrag  iiber  den  Einfluss  des  alkalischen  Mineralwassers  auf  Stick- 
stoff- und  Harnsaureausscheidung.     Therap.  Monatsh.,  18,  69  (1904). 

1°  Genth.  Untersuchungen  iiber  den  Einfluss  des  Wassertrinkens  auf  den  Stoffwechsels. 
Wiesbaden,  1856. 

11  G.  Kobler.  Ueber  einiger  Bezeihungen  der  Diurese  zur  Harnstoff-  und  Harnsaure- 
ausscheidung, insbesondere  bei  den  Compensationsstorungen  der  Herzkranken.  Wien. 
khn.  Wochenschrift,  353  and  375  (1891),  and  Maly's  Jahresb.  iiber  die  Fortschritte  der 
Thierchemie,  21,  431  (1891). 

i^Husches.  Ueber  der  N-Bilanz  in  den  verschiedenen  Stadien  der  Herzkrankheiten. 
Zeitschr.  fiir  kUn.  Med.,  26,  44  (1894). 

13  B.  Laquer.  Ueber  die  Ausscheidungsverhiiltnisse  der  Alloxurkorper  im  Harne  von 
Gesimden  und  Kranken.     Verhandl.  des  14t  Kongr.  fiir  innere  Medizin,  333  (1896). 

1*  R.  Burian  und  H.  Schur.  Ueber  die  Stellung  der  Purinkorper  im  Menschlichen  Stoff- 
wechsel.     2.  Mitth.     Pfliiger's  Archiv,  87,  239   (1901). 


Physiology  245 

Dapper  ^  could  not  find  that  the  drinking  of  water  containing 
common  salt  has  any  effect  on  the  excretion  of  uric  acid.  Bencke,- 
who  used  the  inaccurate  Heinz  method  of  determination,  found 
the  uric  acid  increased  in  two  cases,  and  decreased  in  one  case 
after  use  of  water  containing  sodium  chloride.  After  Friedrich- 
schaller  bitter  water,  which  contains  chiefly  the  sulphates  and 
chlorides  of  sodium  and  magnesium,  a  decreased  excretion  of 
uric  acid  was  found  by  Hosier  ^  and  by  Markwald.^  They  used 
the  Heinz  method  for  determining  uric  acid.  Seegen,^  who  used 
the  Heinz  method  for  analysis,  and  Ludwig,^  who  used  an  accurate 
method,  found  that  the  excretion  of  uric  acid  is  diminished  by 
Carlsbad  water,  which  contains  chiefly  NajSO^,  Na^COg,  and  NaCl. 

It  seems  probable,  then,  that  the  amount  of  water  taken  has 
but  little  effect  upon  the  quantity  of  uric  acid  excreted.  The  effect 
of  water  containing  sodium  chloride  is  very  slight.  Water  con- 
taining sodium  sulphate  seems  to  cause  a  slight  decrease  in  the 
excretion  of  uric  acid. 

SALICYLIC    ACID 

A  great  many  observers  have  obtained  good  clinical  results  in 
gout  from  salicylic  acid  preparations.  Only  Noel-Paton^  found 
decreased  excretion  of  uric  acid  after  administration  of  salicylic 
acid.  He  used  dogs  in  his  experiment.  Kumagawa,^  on  the 
other  hand,  found  that  salicylic  acid  increases  the'  excretion  of 
uric  acid  in  dogs.  In  man,  salicylic  acid  has  been  found  to  pro- 
duce an  increase  in  the  excretion  of  uric  acid  by  Byasson,''  Marrot,^" 

1  Dapper.  Ueber  den  Einfluss  der  Kochsalzquellen  (Kissengen,  Homburg)  auf 
den  Stoffwechsel  beim  Menschen  und  die  sogennante  "  curgemasse  "  Diat.  Zeitschr.  fiir 
klin.  Med..  30,  371  (1896). 

-  Bencke.     Ueber  Nauheimer  Soolthermen,  1859. 

3  F.  Hosier.  Ueber  die  Wirkung  des  Friedrichshaller  Bitterwasser.  Arch,  des  Vereins 
fur  gemeinschaft.  Arbeiten  zur  Forderung  der  Wissenschaft.     Heilkunde,  5,   1   (1861). 

^  B.  Markwald.  Ueber  die  Wirkungen  des  Friedrichshaller  Bitterwassers  und  seinen 
Einfluss  auf  den  Stoffwechsel.     Deutsche  med.  Wochenschrift,  12,  391  (1886). 

=  Seegen.  Physiologisch-chemische  Untersuchungen  iiber  den  Einfluss  des  Karlsbader 
Mineralwassers  auf  den  Stoffwechsel.     Wien.  med.  Wochenschrift,  10,  321  and  340  (1860). 

•^  V.  Ludwig.  Ueber  den  Einfluss  des  Karlsbader  Wassers  auf  den  Stoffwechsel.  Cen- 
tralblatt  fur  innere  Medizin,  17,  1153  und  1177  (1896). 

'  D.  Noel-Paton.  On  the  Nature  of  the  Relationship  of  Urea  Formation  to  Bile  Secre- 
tion.    Journ.  Anat.  and  Physiol.,  20,  114,  265  (1886). 

8  M.  Kumagawa.  Ueber  die  Wirkung  einiger  antipyretische  Mittel  auf  den  Eiweis- 
sumsatz  im  Organismus.     Virchow's  Archiv,  113,  134  (1888). 

^  H.  Byasson.  Etude  sur  la  transformation  de  I'acide  saUcylique  ingerd  par  I'homme. 
Jour,  de  Therapeutique,  4,  721   (1877). 

w  E.  Marrot.  De  Taction  du  salicylate  de  soude  dans  le  rheumatisme  aigu.  Examin 
de  Tuiine  et  du  sang.     Arch.  g^n.  de  M^d.,  7  s^r.,  3,  142  (1879). 


246      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Lecorche  and  Talamon/  See,^  Lecorche,^  *^^iopin,^  Herter 

and  Smith,^  Tanszk  and  Vas/  F.  Levit  "^^eidner/" 

C.   Levison,"  Lewandowski/^    Singer ,^^ 
Waldvogel/^  and  Schreiber  and  ZaudyJ 

This  high  excretion  of  uric  acid  is  attribr 
to  different  causes.  According  to  Levison, 
the  sahcyHc  acid  increases  the  number  - 

increased  excretion  of  uric  acid  is  paraU  ^d 

leucocytosis.     Schreiber  and  Zaudy  "  coulf'  .u  there 

is  any  relation  between  the  number  of  leucoc  .na  -ue  excretion 

of  uric  acid.  Haig  and  others  attribute  to  salicylic  acid  the  same 
action  as  they  do  to  the  alkalies.  They  believe  that  the  salicylic 
acid  dissolves  the  uric  acid  found  in  various  parts  of  the  body  and 
"  washes  "  it  out.  This  cannot  be  so.  Schreiber  and  Zaudy  ^^ 
found  that  if  three  grams  salicylic  acid  per  day  are  given  for  five 
days,  there  is  at  first  an  increased  excretion  of  uric  acid.  This 
decreases  in  a  few  days  to  the  normal  amount.  According  to 
Haig,  this  is  due  to  the  fact  that  the  uric  acid  in  the  body  is  com- 

1  Lecorche  et  Talamon.  De  Paction  du  salicylate  de  soude  sur  I'ur^e  I'acide  urique  et 
I'acide  phosphorique.     R^v.  mensuelle  de  mM.  (1880). 

2  See.     Husemann  Arzneimittellehre  313(1883). 

3  Lecorche.    Traits  de  la  Goutte,  Paris  (1884). 

*  E.  Salom^.  Ueber  den  Einfluss  des  salicylsauren  Natrons  auf  die  Stickstoff-  und 
Hamsaureauascheidung  beim  Menschen.  Schmidt's  Jahrb.,  209,  133  (1886),  and  Wien. 
med.  Jahrb.,  4,  463  (1885V 

5  Chopin.  Ausscheidung  der  Salicylsaure.  Bull.  g^n.  de  Th^rap.  (1889),  Feb.,  and  Maly's 
Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  19,  193  (1889). 

8  C.  Herter  and  E.  Smith.  OlDservations  on  the  excretion  of  uric  acid  in  health  and 
disease.     N.  Y.  Med.  Journ.,  June  4,  1892. 

'  F.  Tanszk  imd  B.  Vas.  Ueber  den  Einfluss  einiger  Antipyretica  auf  den  Stoffwechsel. 
Ungar.  Arch.  f.  Med.,  1,  204  (1892),  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie. 
22,   438   (1892). 

*  F.   Le\'ison.     Die  Harnsaure  diathese.     Berl.  (1893). 

8  K.  Bohland.  Ueber  den  Einfluss  des  salicylsauren  Natrons  auf  die  Bildung  und 
Ausscheidung  der  Harnsaure.     Centralblatt  fiir  innere  Medizin,  17,  70  (1896). 

1°  Weidner.  Ueber  die  Einwirkung  schweisstreibender  und  schweisswidriger  mittel 
auf  den  Leucocytengehalt  des  Blutes  beim  Menschen.     Inaug.  Dissert.,  Bonn  (1896). 

11  C.  Le-^dson.  Ueber  den  Einfluss  einiger  medicamente  auf  Harnsaureausscheidung  und 
Leukocytenzahl.     Inaug.    Dissert.,    Diisseldorf    (1897). 

12  M.  Lewandowski.  Versuche  iiber  den  Einfluss  der  Benzoesaure  auf  die  Harnsaure- 
bildung.     Zeitschr.  fiir  klin.  Med.,  40,  202  (1900). 

13  H.  Singer.  Ueber  Aspirin.  Beitrage  zur  Kenntniss  der  Salicywirkung.  Pfliiger's 
Archiv,  84,  527  (1901). 

i^H.  Ulrici.  Ueber  pharmakologische  Beeinflussung  der  Harnsaureasusscheidung. 
Arch,  fiir  exp.  Path.  u.  Pharm.,  46,  321  (1901). 

1*  Schreiber  und  Waldvogel.  Beitrage  zur  Kenntniss  der  Harnsaureausscheidung 
unter  physiologischen  und  pathologischen  Verhaltnissen.  Arch,  fiir  exp.  Path.  u.  Pharm., 
42,  69  (1899). 

I''  Schreiber  und  Zaudy.  Zur  Wirkung  der  Salicylpraparate,  insbesondere  auf  die 
Harnsaure  und  die  Leucocyten.     Deutsche  Arch,  fiir  klin.  Medizin,  62,  242  (1899). 


Physiology  247 

pletely  "-Wi^Jaed;,  '  .,  But,  if  on  the  sixth  day  the  dose  of 
salicylic  acici  is  4j.j  ,/:i-  here  is  again  an  increase  in  the  amount 
of  uric  acid  exc^-i;  ,  )wing  that  Haig's  explanation  is  wrong. 

According  to  "^  '  i,^  should  not  give  salicylic  acid  in  gout. 

He  thinks  that;^y  ,.|  ased  excretion  of  uric  acid  after  this  drug 
indicates  an  incre;V-j  '  formation  which  is  bad  for  the  gouty.  It 
will  be  remei;;^  hat  Burian^  found  salicylic  acid  to  increase 

the  rate  of  (./  ,,  ,  ni  by  which  uric  acid  is  formed  from  the 
purin  bases  ']'Q-JK  ^^,  xperiments  on  autolysis;  whether  or  no  this 
has  any  beariif;,,      _  ih^  question  we  cannot  say. 

QUINIC   ACID 

We  have  already  spoken  of  the  theory  of  uric  acid  formation 
on  which  the  use  of  quinic  acid  has  been  based.  Briefly,  the 
good  clinical  effects  of  the  citron  cure,  cherry  cure,  and  other  fruit 
cures  led  to  a  search  for  the  active  principle  in  these  fruits.  Ac- 
cording to  Weiss,  this  is  quinic  acid  [tetroxybenzoic  acid, 
CeH7(OH)4COOH],  which  he  found  decreases  the  excretion  of 
uric  acid.  He  thinks  that  uric  acid  is  normally  formed  in  the 
body  by  the  conjugation  of  glycocoll  and  some  other  compound, 
and  that  when  quinic  acid  is  given,  the  glycocoll  is  diverted  to 
form  hippuric  acid  by  conjugation  with  the  benzoic  acid,  w^hich  is 
formed  by  oxidation  of  quinic  acid.  Many  years  before,  Maly- 
and  Latham  ^  recommended  that  benzoic  acid  be  given  in  gout. 
They  stated  that  it  would  probably  decrease  the  excretion  of  uric 
acid  for  this  same  reason.     According    to  Weiss,*  Blumenthal,^. 

'  R.  Burian.  Ueber  die  oxydative  und  die  vermeintliche  synthetische  Bildung  von 
Harnsaure  in  Rinderleberauszug.     Zeitschr.  ftir  physiol.  Chem.,  43,  497  (1905). 

-  R.  Maly.  Ueber  das  Verhalten  der  Oxyhenzoesaure  und  Paraoxybenzoesaure 
in  der  Blutbahn.     Sitzungsber  der  Wiener  Akad.  d.  Wissensch.  65,  2.  Abt.,  39  (1872). 

3  P.  Latham.  Some  Points  on  the  Pathology  of  Rheumatism,  Gout,  and  Diabetes. 
(Croonian  Lectures.)     Lancet  (1886),  1,  626,  673,  723,  771. 

■*  J.  Weiss.  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaurebildung.  Zeit- 
schr.  fiir  physiol.     Chem.,  25,  393   (1898). 

Ibid.  Die  Chinasaure  als  -Antiarthriticum.  Verhandl.  der  Dtsch.  Gesell.  der.  Natur- 
forscher  und  Aerzte,  Miinchen  (1899). 

Ihid.  Eine  neue  Methods  der  Behandlung  der  harnsaure  Diathese.  Berl.  klin. 
Wochenschrift,  36,  297  (1899). 

Ibid.  Weitere  Beitrage  zur  Erforschimg  der  Bedingungen  der  Harnsaurebildung. 
Zeitschr.  fiir  physiol.  Chem.,  27,  216  (1899). 

Ibid.  Die  Erfolge  der  Urosin  Behandlung  bei  harnsaurer  Diathese.  Verhandl.  des 
18t  Kongr.   fur  innere  Medizin,  477  (1900). 

5  Blumenthal.  Ueber  Sidonal,  ein  neues  Heilmittel.  Verhandl.  des  Vereins  fiir  innere 
Med.  zu  Berl.,  19,  480  (1899-1900). 

Blumenthal  und  Lewin.  I'eber  Sidonal,  Chinasaures  Piperazin.  Therapie  der  Gegen- 
wart,  Neue  Folge,  2,  160  (1900). 


248      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Bardet/  Schlayer,^  and  Lewin,^  quinic  acid  decreases  the  ex- 
cretion of  uric  acid,  and  according  to  Huber  and  Lichtenstein,^ 
less  uric  acid  is  formed  from  the  nucleins  after  use  of  quinic 
acid.  On  the  other  hand,  Nicolaier,''  Nicolaier  and  Hagenburg,*' 
Lewandowski,'^  Foerster,^  de  la  Camp,^  Ulrici/°  and  Hupfer^have 
shown  that  quinic  acid  has  no  effect  on  the  excretion  of  uric  acid, 
and  His  ^^  has  shown  that  citron  eating  does  not  increase  the  excre- 
tion of   uric   acid. 

If  Weiss 's  theory  were  true,  we  should  expect  that  benzoic  and 
salicylic  acids  would  decrease  the  excretion  of  uric  acid.  Only 
Ulrici,^"  who  observed  a  very  slight  decrease,  found  this  so  in  the 
case  of  benzoic  acid.  Maly,^^  Lewandowski,^Schreiber  and  Wald- 
vogel,"  and  Nicolaier  and  Hagenburg "  found  that  the  adminis- 
tration of  benzoic  acid  does  not  affect  the  excretion  of  uric  acid. 
Nicolaier  and  Hagenburg  found  likewise  that  cinnamic  acid  does 
not  influence  the  excretion  of  uric  acid.  In  regard  to  salicylic 
acid  we  know  that  this  compound  even  increases  the  excretion 
of  uric  acid. 

^  C.  Bardet.  Traitement  de  la  goutte  et  du  rheumatisme  goutteux  par  le  pidonal  ou 
quinate  de  piperazine.     Bulletin  g&eral  de  th^rapeutique,  141,  518  (1901). 

2  Schlayer.  Erfahrungen  iiber  Sidonal  bei  Gicht.  Therapie  der  Gegenwart.,  N.  F.  2., 
237    (1900). 

5  C.  Lewin.  Beitrage  zum  Hippurpaiirestoffwechsel  des  Menschen.  Zeitschr.  fiir  klin. 
Med.,  42,  371   (1901). 

*  Huber  und  Lichtenstein.  Ueber  Gicht  und  ihre  Behandlungmit  Chinasaure.  Berl. 
klin.  Wochenschrift,  39,  653  (1902). 

5  A.  Nicolaier.  Experimentelles  und  Klinisches  iiber  Urotropin.  Zeitschr.  fiir  klin. 
Med.,  38,  356  (1899). 

Ihid.     Centralblatt  fiir  Stoffwechselkrankheiten  (1900). 

6  A.  Nicolaier  und  J.  Hagenburg.  Ueber  Chinotropin,  (chinasaures  Urotropin).  Cen- 
tralblatt fiir  Stoflwechsel  und  Verdauungskrankheiten,  1,  131  (1900),  and  Maly's 
Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  30,  616  (1900). 

"'  M.  I^ewandowski.  Versuche  iiber  den  Einfiuss  der  Benzoesaure  auf  die  Harnsaure- 
bildung.     Zeitschr.  fiir  klin.  Med.,  40,  202  (1900). 

^  Foerster.  Versuche  iiber  die  Beeinflussung  der  Harnsaureausscheidung  mit  specielle, 
Berucktsichtigung  der  Chinasaure  und  der  cliinasauren  Salze.  Inaug.  Dissert.,  Breslau, 
(1900). 

^  de  la  Camp.  Chinasaure  und  Gicht.  Miinchen  med.  Wochenschrift,  48,  1203  (1901). 

1"  H.  Ulrici.  Ueber  pharmakologfeche  Beeinflussung  der  Harnsaureausscheidung.  Arch, 
fiir  exp.  Path.  u.  Pharmak.,  46,  321  (1901). 

11  F.  Hupfer.  Einwirkung  von  Chinasaure  auf  Harnsaure  und  Hippursaureausscheid- 
ung.     Zeitschr.  fiir  physiol.  Chem.,  37,  302  (1903). 

12  W.  His.  Die  Ausscheidung  von  Harnsaure  im  Urin  der  Gichtkranken  mit  besonderer 
Beriicktsichtigungder  Anfallszeitenund  bestimmter  Behandlungsmethoden.  Deutsche 
Arch,  fiir  klin.  Medizin,  65,   156   (1900). 

13  R.  Maly.  Ueber  das  Verhalten  der  Oxybenzoesaure  und  Paroxybenzoesaure  in  der 
Blutbahu.     Sitzungsber.  der  Wiener  Akad.  d.  Wissenschaft.,  65,  2,  Abt,  39  (1872). 

I'l  Schreiber  und  Waldvogel.  Beitrage  zur  Kenntniss  der  Harnsaureausscheidung 
unter  physiologischen  und  pathologischen  Verhaltnissen.  Arch,  fiir  exp.  Path.  u. 
Pharmak.,  42,  69   (1899). 


Physiology  249 

In  spite  of  the  fact  that  the  evidence  seems  to  show  that  quinic 
acid  does  not  decrease  the  excretion  of  uric  acid,  and  that  Weiss 's 
whole  theory  has  been  shown  to  be  erroneous,  good  clinical  results 
have  been  obtained  in  gout  through  the  use  of  different  quinic  acid 
preparations  by  v.  Leyden,^  Goldscheider,^  Mayer,^  Meyer," 
Ewald,^  Mylius,^  Sternfeld,*  Salfeld,^  v.  Noorden,''  and  Huber  and 
Lichtenstein.''  If  quinic  acid  is  good  in  gout,  it  must  be  on 
account  of  some  action  on  the  metabolism  that  we  do  not  at 
present  understand. 

It  is  interesting  to  note  that  those  drugs  whose  use  in  gout  has 
been  recommended  from  theoretical  reasons  based  on  the  sup- 
posed effect  of  the  drug  on  the  uric  acid  metabolism  have  been 
found  clinically  good  in  the  treatment  of  gout.  These  drugs 
include  the  organic  and  inorganic  alkaline  bodies,  urea,  and  the 
quinic  acid  preparations.  More  careful  experiment  has  shown 
that  the  scientific  theories  on  which  the  use  of  these  drugs  has 
been  based  are  erroneous.  This  is  a  very  peculiar  coincidence. 
Either  a  peculiar  combination  of  accidents  has  made  us  familiar 
with  a  long  series  of  drugs  which  for  some  unknown  reason  are 
good  in  gout,  or  the  methods  of  observation  of  some  good  clini- 
cians are  open  to  criticism. 

ALCOHOL 

According  to  Ries  ^  and  Pfeiffer,"  alcohol  drinking  decreases 
the  excretion  of  uric  acid.     Von  Jaksch  ^^  found  that  alcoholic 

'v.  Leyden,  and  also  Goldscheider.  Discussion  of  Blumenthal's  article:  Ueber  Sidonal 
ein  neues  Gichtmittel.  Verhandl.  des  Vereins  fiir  innere  Medizin,  in  Berlin,  5  Mai,  19, 
480   (1899-1900). 

-J.  Mayer,  E.  Meyer,  vind  Ewald.  In  discussion  of  Blumenthal's  article:  Ueber 
Sidonal,  ein  neues  Gichtmittel.  Verhandl.  der  Vereins  fiir  innere  Medizin,  Berl.,  19, 
480    (1899-1900). 

3  Mylius.  Ueber  die  Einwirkung  des  Sidonals  bei  Gicht.  Therapeutische  Monatshefte 
14,  658  (1900). 

^  H.  Sternfeld.  Die  Chinasaure,  ein  neues  Heilmittel  gegen  Gicht.  Miinchen  med. 
Wochenschrift,  48,  260  (1901). 

'  Salfeld.  Zin-  Behandlung  der  Gicht  mit  Chinasaure.  Miinchen  med.  Wochenschrift, 
48,  633  (1901). 

"v.  Noorden.  Ueber  Urol,  (chinasaures  Harnstoff).  Centralblatt  fiir  Stoffwechsel- 
und  Verdauungskrankheiten,  Sept.,   1901. 

^  Huber  und  Lichtenstein.  Ueber  Gicht  imd  ihre  Behandlung  mit  Chinasaure.  Berl. 
klin.  Wochenschrift,  39,  653  (1902). 

s  L.  Ries.  Ueber  den  Einfluss  des  Alkohols  auf  den  Stoffwechsel  des  Menschen.  Zeitschr. 
fiir  klin.  Med.,  2,  1  (1881). 

8  E.  Pfeiffer.  Die  Natur  und  Behandlung  der  Gicht.  Verhandl.  des  8t  Kongr.  fiir 
mnere  Medizin,  166  (1889). 

1°  R.  von  Jaksch.  Der  Weingeist  als  Heilmittel.  Verhandl.  des  7t  Kongr.  fiir  innere 
Medizin,  86  (ISSS). 


250      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

liquors  decrease  very  slightly  the  excretion  of  uric  acid  in  children. 
Weiss  ^  found  that  cognac  decreases  very  slightly  the  excretion 
of  uric  acid,  and  Laquer  ^  that  beer,  wine,  and  whiskey  have  the 
same  effect. 

Chittenden,^  and  Donogany  and  Tibald  *  found  that  alcohol 
increases  the  excretion  of  uric  acid  in  dogs.  According  to  Schultz,^ 
Herter,^  and  Chotzen,^  the  same  is  true  in  man.  Rosenfeld  ** 
found  that  beer  drinking  increases  the  excretion  of  uric  acid. 
Beer,  ale,  and  porter  contain  from  .002  to  .006  per  cent  of  purin 
bases  according  to  Hall.^  This  would  lead  us  to  expect  increased 
excretion  of  uric  acid  from  these  liquors. 

Schreiber  ^^  and  Haeser  ^'  could  not  find  that  alcohol  has  any 
effect  on  the  excretion  of  uric  acid.  Herrmann  ^^  and  Leber  ^^  ad- 
ministered malt  wine,  Herter  and  Smith  ^*  champagne  and  whis- 
key, and  Rosemann  ^^  cognac,  but  in  no  case  was  there  any  increase 
in  the  excretion  of  uric  acid. 

Chittenden  and  Beebe  ^^  have  experimented  with  whiskey,  beer, 

1  J.  Weiss.  Ueber  den  Einfluss  von  Alkohol  und  Obst  auf  die  Harnsaurebildung. 
Miinchen  med.  Wochenschrift,  48,  1048  (19011. 

^  liEquer.  Ueber  die  Ausscheidungsverhaltiiissen  der  Alloxurkorper  im  Harne  von 
Gesunden  und  Kranken.     Verhandl.  der  14t  Kongr.  fiir  innere  Medizin,  33  (1896). 

8  R.  Chittenden.  The  Influence  of  Alcohol  on  Protein  Metabolism.  Journ.  of  Physiol., 
12,  220    (1891). 

*  J.  Donogany  und  N.  Tibald.  Ueber  den  Einfluss  des  Alkohols  auf  den  Eiweisszer- 
faU-im  Organismus.  Ungarisches  Arch,  fiir  khn.  Medizin,  3,  189  (1894),  Maly's  Jahresb. 
iiber  die  Fortschritte  der  Thierchemie,  24,  552  (1894). 

■''  E.  Schultz.  Ueber  den  Einfluss  der  Nahrung  auf  die  Ausscheidung  der  amidartigen 
Substanzen.     Pfliiger's  Archiv,  45,  401  (1889). 

^  C.  Herter.  Some  Practical  Points  Regarding  the  Excessive  Excretion  of  Uric  Acid. 
N.  Y.  Med.  Journ.,  58,  8  (1893). 

^  Chotzen.     Zur  Frage  der  Fleischersatzmittel.     Inaug.  Dissert.,  Breslau  (1897). 

^  G.  Rosenfeld.  Des  Einfluss  des  Alkohols  auf  den  Organismus.  Wiesbaden  (1901). 
Centralblatt  fur  innere  Medizin,  21,  47  (1901). 

^  J.  Hall.  Vegetabilische  Nahrung  und  Getranke  bei  Gicht  und  Nephritis.  Berl. 
klin.  Wochenschrift,   40,  868   (1903). 

1"  Schreiber.     Ueber  die  Harnsaure,  38,  Stuttgart  (1899). 

'■1  H.  Haeser.  Der  Einfluss  des  Alkohols  auf  die  Harnsaui'eausscheidung.  Inaug. 
Dissert.,    Greifswald    (1901). 

^^  A.  Herrmann.  Ueber  die  Abhangigkeit  der  Harnsaureausscheidung  von  Nahrungs- 
und  Genussmitteln  mit  Rucksicht  auf  die  Gicht.  Deutsche  Arch,  fiir  kUn.  Medizin,  43, 
273  (1888). 

'^  H.  Leber.  Zur  Physiologie  und  Pathologic  der  Harnsaureausscheidung  beim  Menschen 
Berl.  klin.  Wochenschrift,  34,  956  (1897). 

1^  Herter  and  E.  Smith.  Observations  on  the  Excretion  of  Uric  Acid  in  Health  and 
Disease.     N.  Y.  Med.  Journ.,  55,  617  (1892). 

15  R.  Rosemann.  Ueber  den  Einfluss  des  Alkohols  auf  die  Harnsaureausscheidung. 
Deutsche  med.  Wochenschrift,  27,  531  (1901). 

16  R.  Chittenden  and  S.  Beebe.  The  Effect  of  Alcohol  and  Alcoholic  Fluids  upon  the 
Excretion  of  Uric  Acid  in  Man.  Proc.  of  the  Am.  Physiol.  Soc.  1903,  Am.  Journ.  Physiol., 
9,  1    (1903). 


Physiology  251 

and  wine.  They  administered  these  beverages  to  the  extent  of 
from  70  to  80  cubic  centimeters  of  absolute  alcohol  per  day. 
Whiskey  had  scarcely  any  effect  on  the  uric  acid  excretion.  After 
wine  and  beer  there  was  a  slightly  increased  excretion  of  uric  acid. 

According  to  Beebe/  alcohol  increases  the  excretion  of  uric  acid 
and  the  purin  bodies.  It  seems  to  prevent  the  complete  oxidation 
of  the  purin  bodies  of  the  food,  for  when  it  is  taken  without  food 
it  does  not  increase  the  excretion  of  uric  acid,  and,  further,  the 
maximum  excretion  of  uric  acid  after  taking  alcohol  and  food 
occurs  at  the  same  time  as  when  the  alcohol  is  not  taken. 

According  to  Schittenhelm,^  the  purin  bodies  in  the  feces  are 
decreased  in  alcoholic  stools. 

The  trouble  with  most  of  the  experimental  work  concerning 
the  effect  of  alcohol  and  other  drugs  on  the  excretion  of  uric 
acid  is  that  the  diet  has  not  been  so  regulated  as  to  keep  the 
amount  of  uric  acid  excreted  constant  from  day  to  day.  The 
greater  part  of  the  work  has  not  been  done  recently  enough  to 
take  advantage  of  our  present  knowledge  concerning  the  meta- 
bolism of  uric  acid.  We  now  know  enough  about  the  effect  of 
different  foodstuffs  on  the  excretion  of  uric  acid  to  be  able  to  keep 
the  excretion  of  uric  acid  fairly  constant  by  regulating  the  diet. 

According  to  Neumayer  ^  beer  and  white  wine  increase  the  so- 
called  "  free  "  uric  acid,  which  is  given  up  to  a  uric  acid  filter. 
Red  wine  and  pure  alcohol  have  no  effect.  Rosenfeld  *  and 
Glaser,^  too,  found  that  alcohol  causes  a  large  precipitate  of  uric 
acid  in  the  urine. 

COLCHICUM 

Colchicum  is  a  drug  which  has  long  been  used  as  a  therapeutic 
agent  in  gout.  Only  His,**  Ransome,^  and  Liebreich  *  have 
studied  its  effect  on  the  excretion  of  uric  acid  in  recent  times. 

1  S.  Beebe.  The  effect  of  alcohol  and  alcoholic  fluids  upon  the  excretion  of  uric  acid 
in  man.     Am.  Journ.  of  Physiol.,  12,  13  (1904). 

^  A.  Schittenhelm.  Die  Purinkorper  der  Faces  nebst  untersuchungen  iiber  die  Pur- 
inbasen  der  Darmwand,  der  Galle  und  des  Pankreassaftes.  Arch,  ftir  klin.  Medizin, 
81,  423  (1904). 

3  H.  Neumayer.  Discussion  in  d.  Versamml.  des  14t  Kongr.  fiir  innere  Medizin  (1896), 
14,  24,  and  Ueber  die  Therapie  des  harnsauren  Diathese.  Verhandl.  des  aerztliches  vereias 
in  Miinchen  9  Marz,  1898,  und  Deutsche  med.  Wochenschrift.  24,  vereins  Beilage  60  (1898). 

^  R.  Rosenfeld.     Der  Einfluss  des  Alkohols  auf  der  Organismus.       Wiesbaden,   1901. 

^  Glaser.  Ueber  den  Einfluss  alkoholischer  Getranke  auf  das  Harnsediment  der 
normalen  Menschen.     Deutsche  med.  Wochenschrift,  17,  1193  (1891). 

6  W.  His.     Untersuchungen  an  Gichtkranken.     Wien.  med.  Blatter,  19,  291  (1896). 

7  C.  Ransome.     Colchicum  in  the  Treatment  of  Gout.     Medical  News,  82,  1105  (1903). 
*  Liebreich.     Artikel  —  Colcliicum —  in  Encyklopadie  der  Therapie    (1896),  1,  757. 


252      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

His  and  Ransome  could  not  find  that  it  has  any  effect.  According 
to  Liebreich,  the  action  of  colchicum  on  the  excretion  of  uric 
acid  depends  somewhat  on  the  condition  of  the  kidneys.  Among 
older  experimenters,  Noel-Paton  ^  found  increased  uric  acid  in 
dogs,  and  Mairet  and  Combemale  ^  increased  uric  acid  in  man  after 
colchicum.  Graves  and  Bresster  ^  and  Lecorche,*  on  the  other 
hand,  found  decreased  excretion  of  uric  acid.  Moss  ^  could  not 
find  that  colchicum  has  any  effect. 

ANTIPYRIN,  ANTIFEBRIN,  AND  PHENACETIN 

The  evidence  in  the  case  of  antipyrin  is  contradictory.  Accord- 
ing to  Robin  ^  and  Levison,^  the  administration  of  antipyrin 
causes  an  increased  excretion  of  uric  acid  in  man.  Kumagawa  ^ 
found  the  same  result  in  dogs.  Chittenden^  and  Horbaczewski,^" 
on  the  other  hand,  observed  a  slightly  decreased  excretion  of  uric 
acid  in  man  after  antipyrin.  Umbach,"  Bohland,^^  Tanszk  and 
Vas,^^  and  Stroux  "  could  not  observe  that  this  drug  has  any  effect 
on  uric  acid  excretion. 

Chittenden  and  Taylor  ^^  observed  a  decrease  in  the  excretion 

^  D.  Noel-Paton.  On  the  Nature  of  the  Relationship  of  Urea  Formation  to  Bile  Secre- 
tion.    Journ.  of  Anat.  and  Physiol.,  20,  114,  and  265  (1886). 

^  A.  Mairet  et  Combemale.  Recherches  sur  le  mode  d'action  de  la  colchicine  prise 
a  dose  therapeutique  et  la  mecanisme  de  cette  action.     Comptes  rendus,  104,  515  (1887). 

3  Graves  und  Bresster.     Khnische  Beobachtungen.     Leipzig  (1847). 

4  Lecorchf?.     Traite  de  la  Goutte,  Paris  (1884). 

■5  Moss.  On  the  Action  of  Potash,  Soda,  Lithia,  Lead,  Opium,  and  Colchicum  on  the 
■  Urine.      Am.  Journ.  of  Med.  Sciences,  41,  384  (1861). 

8  A.  Robin.  Wirkung  des  Antipyrins  auf  die  Ernahrung.  Bull,  de  I'acad.  de  med. 
(1887),  49;  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  18,  267  (1888). 

'  C.  Levison.  Ueber  den  Einfluss  einiger  Medicamente  auf  Harnsaureausscheidung  und 
Leukocytenzahl.    Inaug.  Dissert.,  Diisseldorf  (1897). 

*  M.  Kumagawa.  LTeber  die  Wirkung  einiger  antipyretischer  Mittel  auf  den  Eiweissum- 
satz  im  Organismus.     Virchow's   A.rchiv,   113,   134  (1888). 

^  R.  Chittenden.  Ueber  den  Einfluss  von  Urethan,  Antipyrin,  und  Antifebrin  auf  den 
Eiweissumsatz.     Zeitschr.  fiir  Biologie,  25,  496  (1889). 

1"  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xanthin  - 
basen,  sowie  der  Entstehung  der  Leukocyten  im  Saugethierorganismus.  Monatshefte 
fiir  Chemie,  12,  221  (1891). 

'1  C.  Umbach.  -Ueber  den  Einfluss  des  Antipyrins  auf  die  Stickstoffausscheidung. 
Arch,  fur  exp.  Path.  u.  Pharm.,  21,  161  (1886). 

12  K.  Bohland.  Ueber  den  Einfluss  einiger  Arzneimittel  auf  die  Bildung  und  Aus- 
scheidung  der  Harnsaure.     Miinchen  med.  Wochenschrift,  46,  505  (1899). 

13  F.  Tanszk  und  B.  Vas.  Ueber  den  Einfluss  einiger  Antipyretica  auf  den  Stoffwechsel. 
Ungar.  Arch,  fiir  Med.,  1,  204  (1892),  Maly's  Jahresb.  uber  die  Fortschritte  der  Thier- 
chemie, 22,  438  (1892). 

1*  H.  Stroux.  Ueber  die  Beeinflussung  der  Harn?aure  durch  verscheidene  Arzneimittel. 
Inaug.  Dissert.,  Bonn  (1896). 

15  Chittenden  and  Taylor.  The  Influence  of  Urethane,  Paraldehyde,  Antipyrine,  and 
Antifebrin  on  the  Proteid  Metabolism.  Studies  from  the  Laboratory  of  Physiological 
Chemistry,  Yale   (1887-88). 


Physiology  253 

of  uric  acid  after  antifebrin.     Tanzsk  and  Vas  ^  could  not  find 
that  it  has  any  effect. 

According  to  Stroux  ^  and  Bohland,^  phenacetin  has  very  little 
influence  on  the  excretion  of  uric  acid.  According  to  Levison/ 
this  drug  increases  the  excretion  of  uric  acid. 

QUININE 

Only  Richter '"  observed  no  effect  of  quinine  on  the  excretion 
of  uric  acid.  Decreased  excretion  of  uric  acid  after  admin- 
istration of  quinine  has  been  observed  in  man  by  Ranke,^ 
Binz/  Kerner,^  Chittenden  and  Whitehouse,^  Prior/"  Levison/ 
Horbaczewski,"  Stroux,^  and  Bohland^;  in  the  dog  by  Kuma- 
gawa/^  and  in  the  cat  by  Mendel  and  Brown. ^^  According  to 
Zagari  and  Pace/^  quinine  increases  the  excretion  of  uric  acid 
in  man. 

'  F.  Tanzsk  und  B.  Vas.  Ueber  den  Einfluss  einiger  Antipyretica  auf  den  StofFwechsel. 
Ungar.  Arch,  fiir  Med.,  1,  204  (1892),  Maly's  Jahresb.  iiber  die  Fortschritte  der 
Thierchemie,  22,  438  (1892). 

2  H.  Stroux.  Ueber  die  Beeinflussung  der  Harnsaure  durch  verscheidene  Arzneimittel. 
Inaug.  Dissert.,  Bonn  (1896). 

3  K.  Bohland.  Ueber  den  Einfluss  einiger  Arzneiniittel  auf  die  Bildung  und  Ausscheid- 
ung  der  Harnsaure.     Miinchen  med.  Wochenschrift,  46,  506  (1899). 

*  C.  Le'v'ison.  Ueber  den  Einfluss  einiger  Medicamente  auf  Harnsaureausscheidung  mad 
Leukocytenzahl.     Inaug.  Dissert.,  Diisseldorf  (1897). 

^  P.  Richter.  Ueber  Harnsaureausscheidung  und  Leukocyten.  Zeitschr.  fiir  klin . 
Med.,  27,  290  (1895). 

*  H.  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidimg  der  Harnsaure 
beim  Menschen.     Mtinchen   (1858). 

"  C.  Binz.  Pharmakologische  Studien  iiber  Chinin.  Virchow's  Archiv,  46,  67,  and 
129  (1869). 

^  G.  Kerner.  Beitrage  zur  Keimtniss  der  Chininresorption.  Pfliiger's  Archiv,  3,  93 
(1870). 

^  Chittenden  and  Whitehouse.  Influence  of  Cinchonidin  Sulphate  on  Metabolism. 
Studies  from  the  Laboratory  of  Physiological  Chemistry,  Sheffield  Scientific  School,  Yale 
College  (1884-85). 

1"  Prior.  Ueber  den  Einfluss  des  chinin  auf  den  Stoff'wechsel  des  gesunden  Organismus. 
Pfluger's  Archiv,  34,  237  (1884). 

11  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Harnsaure  und  der  Xanthin- 
basen,  sowie  der  Entstehung  der  Leukocyten  im  Saugethierorganismus.  Monatshefte  fur 
Chemie,  12,  221  (1891). 

^'^  M.  Kumagawa.  Ueber  die  Wirkung  einiger  antipyretisehen  Mittel  auf  den  Eiweis- 
sumsatz  in  Organismus.     Virchow's  Archiv,   13,   134  (1888). 

13  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the 
Cat,  Especially  on  the  Excretion  of  L'ric  Acid  and  Allantoin.  Am.  Journ.  of  Physiol., 
3,    261    (1901). 

1^  G.  Zagari  e  D.  Pace.  La  genesi  dell'  aeido  urico  e  la  gotta  in  riguardo  alia  patogenesi 
e  all'  indirizzo  terapeutico.  Napoli,  1897.  Centralblatt  fiir  innere  Medizin,  19,  816 
(1898). 


254    ■  The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 


TANNIC  ACID  AND   TANNIN 

According  to  Levison/  Dolff,^  and  Bohland,^  the  administra- 
tion of  tannic  acid  causes  a  decrease  in  the  excretion  of  uric 
acid.  The  same  is  true  of  tannin,  according  to  Levison  *  and 
Sabrezes  and  Frezal.'^  Neither  Weiss  ^  nor  Ulrici  ^  could  find  that 
tannin  has  any  influence  on  the  quantity  of  uric  acid  excreted. 
Tannic  acid  has  no  effect  on  the  excretion  of  uric  acid  in  cats, 
according  to  Mendel  and  Brown. ^ 

LEAD 
In  view  of  the  fact  that  lead  poisoning  sometimes  seems  to  lead 
to  gouty  changes,  it  is  rather  surprising  that  but  few  attempts 
have  been  made  to  study  the  effect  of  lead  poisoning  on  the  excre- 
tion of  uric  acid.  According  to  Garrod,^  who  used  the  inaccurate 
Heinz  method  of  determination,  there  is  a  very  slight  decrease 
in  the  excretion  of  uric  acid  in  lead  poisoning.  This  was  confirmed 
by  Bouchard  ^^  and  Gaucher."  Surmont  and  Brunelle  ^^  state 
that  when  the  lead  poisoning  lasts  but  a  short  time,  there  is  a 
decreased  excretion  of  uric  acid;  when  the  lead  poisoning  extends 
over  a  long  period,  the  excretion  of  uric  acid  is  increased.  Luthje  ^^ 
could  not  find  that  there  is  any  change  in  the  excretion  of  uric 
acid  in  lead  poisoning  in  dogs. 

1 C.  Levison.  Ueber  den  Einfluss  eiiiiger  Medicamente  auf  Harnsanreausscheidung 
und  Leukocytenzahl.     Inaug.  Dissert.,  Bonn   (1897). 

^  F.  Dolff.  Ueber  den  Einfluss  von  nucleinreicher  Nahrung  und  Acidum  tannicum  auf 
den  Hamsaureausscheidung  beim  Menschen.     Inaug.  Dissert.,  Bonn  (1898). 

3  K.  Bohland.  Ueber  den  Einfluss  Arzneimittel  auf  die  Bildung  und  Ausscheidung 
der  Harnsaure.     Miinchen  med.  Wochenschrift,  46,  505  (1899). 

*F.  Levison.  Zur  Lehre  von  der  Pathogenese  der  Gioht.  Zeitsohr.  fiir  klin.  Med.,  26, 
293   (1894). 

s  J.  Sabrezes  et  M.  Fr^zal.  Action  du  tannin  sur  la  diurese.  Journ.  de  phys.  et  de 
path,  g&eral,  1,  221   (1899). 

6  J.  Weiss.  Weitere  Beitrage  zur  Erforschung  der  Bedingungen  der  Harnsaure-Bildung. 
Zeitschr.  fiir  physiol.  Chem.,  27,  216   (1899). 

'  H.  Ulrici.  Ueber  pharmakologisciie  Beeinflussung  der  Hamsaureausscheidung. 
Arch,  fur  exp.  Path.  u.   Pharm.,  46,   321   (1901). 

8  L.  Mendel  and  E.  Brown.  Observations  on  the  Nitrogenous  Metabolism  of  the  Cat, 
Especially  on  the  Excretion  of  Uric  Acid  and  Allantoin.  Am.  Journ.  of  Physiol.,  3,  261 
(1900). 

8  A.  Garrod.     The  Nature  and  Treatment  of  Gout. 

"  Bouchard.  Leeons  sur  les  maladies  par  ralentissement  de  la  nutrition.  Paris 
(1890). 

"  Gaucher.  Les  troubles  de  la  nutrition  dans  I'intoxication  saturnine.  Revue  de 
m^decine    (1881). 

12  Surmont  et  Brunelle.  Recherches  sur  I'elimination  de  I'azote  urinaire  au  cours  et 
dans  la  convalescence  de  la  colique  saturnine.     Arch.  g^n.  de  mf5d.  (1894). 

"C.  Luthje.     Ueber  Bleigicht.     Zeitschr.  fiir  klin.  Med.,  29,  266  (1896). 


Physiology  255 


OTHER  DRUGS 

Pohl  ^  states  that  spermin  decreases  the  excretion  of  uric  acid, 
and  Richter  ^  that  it  has  no  effect.  According  to  Zagari  and 
Pace,*  spermin  increases  the  excretion  of  uric  acid. 

Umbach  ^  and  Noel-Paton  ^  found  a  slight  decrease  in  the  excre- 
tion of  uric  acid  after  calcium  sulphide. 

According  to  Eckart,^  KoUmann,''  and  Sticker,^  the  inhalation 
of  oxygen  decreases  the  excretion  of  uric  acid.  According  to 
Krafft  ®  and  Honigmann/"  it  has  no  effect. 

Mares, ^^  and  Kiihnau  and  Weiss  ^^  observed  a  slight  increase  in 
the  excretion  of  uric  acid  after  pilocarpin. 

After  urotropin,  Rosenfeld  and  Orgler  ^*  found  the  excretion 
of  uric  acid  decreased,  while  His "  and  Bain  ^^  found  it  un- 
changed. 

1  A.  Pohl.  Einwirkung  des  Spermins  auf  den  Stoffumsatz  bei  Autointoxicationen  im 
Allgemeinen  und  bei  harnsaurer  Diathese  im  Speciellen.  Zeitschr.  fiir  klin.  Med.,  26, 
135    (1S94). 

2  P.  Richter.  Ueber  Hamsaureausscheidung  und  Leukoeyten.  Zeitschr.  fiir  klin.  Med., 
27,  290  (1895). 

3  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  patogenesi 
e  all'  indirizzo  terapeutico.  Napoli,  1897.  Centralblatt  fiir  innere  Medizin,  19,  816 
(1898). 

*  C.  Umbach.  Ueber  den  Einfluss  des  AntipyrLns  auf  die  Stickstoffausscheidung. 
Arch,  fiir  exp.  Path.  u.  Pharm,  21,  161  (1886). 

5  D.  Noel-Paton.  On  the  Nature  of  the  Relationship  of  Urea  Formation  to  Bile  Secre- 
tion.    Journ.  Anat.  and  Physiol.,  20,  114,  and   265  (1886). 

^Eckart.     Die  acute  Gicht  imd  ihre  BehancUung.     Miinchen    (1864). 
^  Kollmann.     Munchen.  arztl.  Intelligenzblatt,    22,    (1869). 

*  G.  Sticker.  Beitrage  zur  Pathologic  und  Therapie  der  Leukamie.  Zeitschr.  fiir 
klin.  Med.,  14,  80  (1888),  and 

Der  Bostock's  Sommerkatarrh  (Heufieber),  in  Nothnagel's  Handbuch  (1896),  4, 
1,  85. 

^.Krafft.  Chemische  Untersuchungen  tiber  den  Einfluss  von  Sauerstoff  Inhalationen 
auf  die  Stickstoffprodukte  im  Ham.  Rev.  med.  de  la  suisse,  Rom.,  4,  295  (1890).  Fort- 
schritte  der  Med.,  7,  776  (1890). 

't"  G.  Honigmann.  Beitrage  zur  Kenntniss  der  Wirkung  von  Sauerstoffeinathmungen 
auf  den  Organismus.     Zeitschr.  fiir    klin.  Med.,  19,  270  (1891). 

^1  F.  Mares.  Sur  I'origine  de  I'acide  urique  chez  rhomme.  Archives  slaves  de  biologic, 
36,  307,  and  Centralblatt  fur  innere  Medizin,  26,  2  :X:i888). 

'2  W.  Kiihnau  und  F.  Weiss.  Weitere  MittheUungen  zur  Kenntniss  der  Hamsaure- 
ausscheidung bei  Leukocytose  und  Hypoleukocytose  sowie  zvu  Pathologic  der  Leukamie. 
Zeitschr.  fiir  klin.  Med.,  32,  482  (1897). 

'3  Rosenfeld  und  Orgler.  Zur  Behandlung  der  harnsauren  Diathese.  Centralblatt 
fur  innere  Medizin,  17,  42  (1896),  and 

G.  Rosenfeld.  Grundzuge  der  Behandlung  der  harnsauren  Diathese.  Verhandl.  des 
14t  Kongr.  fiir  innere  Medizin,  318  (1896). 

1^  W.  His.  Die  Ausscheidung  von  Harnsaure  im  Urin  der  Gicht kranken  mit  besonderer 
Berucktsichtigung  der  Anfallzeiten  und  bestimmter  Behandlungsmethoden.  Deutsche 
Arch,  fiir  klin.  MecUzin,  65,  156  (1900). 

'5  W.  Bain.  The  Influence  of  Some  Modern  Drugs  on  Metabolism  in  Gout.  Brit.  Med. 
Journ.,   1,   243   (1903). 


256      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

According  to  Horbaczewski/  Stroux,^  Bohland,^  and  Levison,"* 
atropin  decreases  the  excretion  of  uric  acid. 

Sticker'^  found  that  arsenic,  and  Ritter  "^  that  N2O  decreases 
slightly  the  excretion  of  uric  acid. 

Stroux,^  Bohland,^  and  Levison  *  could  not  find  that  campheric 
acid  has  any  effect  on  the  uric  acid  excretion. 

According  to  Munzer  and  Palmer/  the  excretion  of  uric  acid 
is  increased  in  carbon  monoxide  poisoning. 

Robin  *  found  decreased  excretion  of  uric  acid  after  thallium. 

Mortessier  ^  could  not  find  that  kola  nut  has  any  effect  on  the 
excretion  of  uric  acid. 

The  replacement  of  NaCl  by  KCl  in  the  food  does  not  influence 
the  excretion  of  uric  acid,  according  to  Herrmann.^" 

BATHS 

After  a  hot  bath,  Laquer  ^^  found  the  excretion  of  uric 
acid  increased.  Formanck  ^^  noticed  a  slight  increase  in  the 
excretion  of  uric  acid  after  hot  baths.  He  found  also  that 
a  single  cold  bath  has  no  effect,  but  that  two  long  cold  baths 
per    day    increase    the    excretion   of    uric    acid.      According   to 

•  Horbaczewski.  Beitrage  zur  Kenntniss  der  Bildung  der  Hamsaure  und  der  Xan- 
thinbasen,  sowie  der  Entstehung  der  Leukocyten  im  Saugethierorganismus.  Monatshefte 
fiir  Chemie,  17,  221   (1891). 

2  H.  Stroux.  Ueber  die  Beeitiflussung  der  Hamsaure  durch  verschiedene  Arzneimittel. 
Inaug.  Dissert.,  Bonn   (1896). 

3  K.  Bohland.  Ueber  den  Einfluss  einiger  Arzneimittel  auf  die  Bildung  und  Aus- 
scheidung  der  Hamsaure.     Miinchen  med.  Wochenschrift,  46,  505  (1899). 

^  C.  I^evison.  Ueber  den  Einfluss  einiger  Medicamente  auf  Harnsaureausscheidung 
und  Leukocytenzahl.     Inaug.  Dissert.,  Diisseldorf  (1897). 

^  G.  Sticker.  Beitrage  zur  Pathologie  und  Therapie  der  Leukamie.  Zeitschr.  fiir  klin . 
Med.,  14,  80  (1888). 

8  Ritter.  Mode  d'action  du  protoxyde  d'azote.  Revue  medical  de  I'Est,  1,  41  (1874), 
Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  4,  191  (1874). 

'  E.  Munzer  und  P.  Palmer.  Ueber  den  Stoffwechsel  des  Menschen  bei  Kohlendunst- 
und  Nitrobenzolvergiftung.     Zeitschr.  fiir  Heilk.,  15,  1  (1894). 

^  A.  Robin.  Physiologische  Wirkung  der  Thalliiun,  seine  therapeutischen  contrain- 
dicationen.  Arch.  d.  Physiol.,  21,  667  (1890),  Maly's  Jahresb.  iiber  die  Fortschritte  der 
Thierchemie,  20,  347  (1890) . 

^  J.  Mortessier.  Influence  du  travail  musculaire  sur  I'elimination  de  la  creatinine. 
Compt.  rend.  soc.  Biol.,  43,  573  (1891),  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thier- 
chemie. 21,  182  (1891). 

1"  A.  Herrmann.  Ueber  die  Abhangigkeit  der  Harnsaureausscheidung  von  Nahrungs- 
und  Genussmitteln  mit  Riicksicht  auf  die  Gicht.  Deutsche  Arch,  fiir  klin.  Medizin,  43, 
273  (1888). 

*i  B.  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  AUoxurkorper  im  Harne  von 
Gesunden  und  Kranken.     Verhandl.  des  14t  Kongr.  fiir  innere  Medizin,  333  (1896). 

*2  Formanck.  Ueber  den  Einfluss  kalter  Bader  auf  die  Stickstoff-  und  Harnsaureaus- 
scheidung beim  Menschen.     Zeitschr.  fiir  physiol.  Chem.,  19,  271  (1891). 


Physiology  257 

Ebstein/  baths  do  not  affect  the  excretion  of  uric  acid. 
Makowiecki,^  who  found  a  slightly  decreased  excretion  of  uric 
acid  after  hot  baths,  used  the  inaccurate  Hay  craft  method  for 
determinino;  uric  acid. 


It  can  be  seen  that  the  results  of  experiments  on  the  effect  of 
drugs  on  the  excretion  of  uric  acid  are  often  contradictory.  In  a 
good  deal  of  the  work  inaccurate  methods  for  the  determination 
of  uric  acid  were  used.  In  most  of  the  work  the  diet  was  not 
carefully  regulated.  We  have  not  criticized  the  experiments 
individually,  since  the  effect  of  drugs  on  the  size  of  the  uric  acid 
excretion  cannot  be  said  to  mean  much  at  the  present  time. 
There  is  no  drug  which  we  can  say  either  decreases  the  formation 
of  uric  acid,  furthers  its  excretion,  hastens  its  further  oxidation, 
or  increases  its  solubility  in  the  blood  or  tissue  fluids. 

1  W.  Ebstein.  The  Regimen  to  be  Adopted  in  Cases  of  Gout.  English  transl.  by  J. 
Scott  (1885). 

^  N.  Makowiecki.  Zur  Frage  der  Einwirkung  desrussischen  Schwitzba  des  auf  Stick- 
stoffumsatz  und  Fettassimilation  und  auf  die  Assimilation  der  stickstoffhaltigen  Bestand- 
theile  der  Nahrung  bei  Gesunden.  Inaug.  Dissert.,  Petersburg  (1888);  Maly's  Jahresb. 
iiber  die  Fortschritte  die  Thierchemie,  18.  289  (1888). 


258      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 


III.    PatKologV 


In  the  section  on  uric  acid  in  pathological  conditions,  we  shall 
consider  chiefly  gout,  although  for  completeness,  a  brief  chapter  on 
uric  acid  in  other  pathological  conditions  will  be  added.  Certain 
authors  have  maintained  that  when  sodium  acid  urate  precipitates 
and  forms  concretions  in  the  tissues  for  any  reason,  these  concre- 
tions cause  either  mechanical  or  chemical  irritation  or  necrosis. 
Others  have  stated  that  the  purin  bases,  the  antecedents  of  uric 
acid,  produce  toxic  symptoms.  The  truth  of  these  facts  has  been 
disputed.  We  shall,  therefore,  precede  our  treatment  of  gout 
itself  by  a  discussion  of  the  action  of  uric  acid  and  the  purin  bases 
in  the  body. 

Toxicology  of  Ueic  Acid  and  the  Purins 

The  action  of  only  hypoxanthin,  xanthin,  guanin,  adenin, 
uric  acid,  and  urates  is  of  interest  to  us.  Caffein  and  theobromin 
are  known  to  have  decided  action  in  the  body,  but  since  they 
affect  the  uric  acid  metabolism  little  if  any,  they  are  of  no  interest 
from  our  standpoint. 

General  Action 

Filehne  ^  obtained  tetanus  in  frogs  after  injection  of  hypoxan- 
thin, and  tetanus  followed  by  cardiac  arrest  after  xanthin.  Ac- 
cording to  Paschkis  and  Pal,^  injections  of  seven  to  ten  milligrams 
of  xanthin  caused  increased  irritability  in  the  muscles  of  frogs. 
This  work  was  confirmed  by  Baldi,^  who  found  that  injections 
into  frogs  of  20  milligrams  of  xanthin  dissolved  in  NajCOg  brings 
about  tetanus,  and  that  smaller  doses  cause  increased  reflex 
irritability.  Gautier  *  obtained  similar  results  after  injection  of 
hypoxanthin  into  guinea  pigs. 

1  E.  Filehne.  Ueber  einige  Wirkungen  des  Xanthins.  Arch,  fiir  Anat.  und  Physiol., 
72   (1886). 

2  Paschkis  und  Pal.     Wien.  med.  Jahrb.  (1886),  611. 

3  Baldi.     La  Terapia  Moderna,  No.  12  (1891). 
*A.  Gautier.     Les  Toxines,  1,  264  (1896). 


Pathology  259 

Schmiedeberg  *  observed  increased  reflex  irritability  of  muscles 
in  pigs  after  injection  of  xanthin,  and  increased  cerebral  irritability 
and  tetanus  after  injection  of  hypoxanthin  dissolved  in  NajCOj. 
This  author  found  that  practically  all  the  members  of  the  purin 
group  with  which  he  experimented  bring  about  increased  reflex 
irritability,  and  therefore  attributed  this  action  to  the  purin 
nucleus  itself.  Differences  in  the  intensity  of  the  action  of  different 
members  of  the  group,  he  suggested,  might  be  due  to  differences 
in  solubility  or  rates  of  absorption.  Uric  acid  itself  seemed  to  be 
inactive  in  frogs. 

According  to  Croftan,^  injection  of  xanthin  or  hypoxanthin  into 
rabbits  causes  increased  blood  pressure  and  cardiac  hypertrophy. 

Hall  ^  could  not  find  that  hypoxanthin  increases  the  blood 
pressure  of  rabbits.  He  gave  small  doses  of  hypoxanthin  daily 
for  fifty  days,  and  found  the  blood  pressure  very  constant.  This 
author  maintains  that  the  blood  pressure  in  Crof tan's  experiments 
was  normal  after  the  hypoxanthin  injections,  and  that  Crof  tan 
took  too  low  values  for  the  normal  blood  pressure. 

According  to  Freudweiler,*  hypoxanthin  and  xanthin  are  toxic 
when  injected  into  rabbits. 

Guanin,  up  to  doses  of  100  milligrams,  is  inactive  in  frogs, 
according  to  Filehne.'^ 

According  to  Paschkis  and  Pal,^  and  Rachford,^  paraxanthin 
is  toxic  and  causes  migraine,  epilepsy,  and  certain  other  diseases. 

Putnam  and  Pfaff  ^  showed  that  Rachford  used  not  paraxan- 
thin, but  a  mixture  of  paraxanthin  and  ammonium  salts,  and 
that  even  this  solution  is  not  toxic  in  mice. 

'  O.  Schmiedeberg.  Vergleichende  Untersuchungen  iiber  die  pharmakologischen 
Wirkungen  einiger  Purinderivate.     Ber.  der  Dtsch.  chem.  Gesell.,  34,  2550  (1901). 

-A.  Croftan.  Role  of  Alloxuric  Bases  in  the  Production  of  the  Cardio- Vascular 
Changes  of  Nephritis.     Am.  Journ.  of  Med.  Sciences,  120,  592  (1900). 

3  1.  Hall.  The  Purin  Bodies  of  Foodstuffs.  Manchester,  Eng.  (1902),  also  I.  HaU. 
Metabolism  in  Gout  and  the  Need  for  Combined  Investigation.  Practitioner,  71,  61 
(1903). 

Ibid.  Beitrage  zur  Kenntniss  der  Wirkung  der  Purinsubstanzen.  Virchow's  Archiv, 
174,  359  (1903). 

■*  M.  Freudweiler.  Experimentelle  Untersuchungen  iiber  die  Entstehung  der  Gicht- 
knoten.     Deutsche  Arch,  fur  klin.  Medizin,  68,  155  (1900). 

•' W.  Filehne.  Ueber  einiger  Wirkungen  des  Xanthins.  Arch.  f.  Anat.  u.  Physiol.,  72 
(1886). 

•*  Paschkis  und  Pal.     Wien.  med.  Jahrb.  (1886),  611. 

'  Rachford  from  Kolisch.  Ueber  Wesen  und  Behandlung  der  uratischen  Diathese. 
Stuttgart   (1895). 

*  J.  Putnam  and  F.  Pfaff.  Disproof  of  Paraxanthin  Poisoning  Theory.  Journ.  of 
Boston  Society  of  Medical  Sciences,  3,  255  (1898). 


260      The  Chemistry,  Physiology ,  and  Pathology  of  l)ric  Acid 

Direct  experiments  with  uric  acid  and  urates  have  not  shown 
that  these  bodies  bring  about  general  toxic  symptoms.  Filehne  ^ 
and  Schmiedeberg  ^  found  uric  acid  inactive  in  frogs.  Filehne 
administered  as  much  as  100  milligrams.  Croftan  ^  fed  uric 
acid  to  dogs,  and  gave  them  injections  of  it  for  long  periods 
without  producing  toxic  symptoms. 

According  to  Stadthagen,^  a  large  dose  of  sodium  acid  urate 
caused  toxic  symptoms  in  a  leukemic  patient.  This  has  not  been 
confirmed.  The  symptoms  might  well  be  due  to  other  causes.  The 
same  may  be  said  concerning  the  headache  observed  by  Hall  ^ 
after  taking  uric  acid  in  the  food.  Haig-'s  ®  statement  that  excess 
of  uric  acid  in  the  blood  causes  irritation  of  the  vasomotor 
nerves,  by  means  of  which  the  blood  pressure  is  raised  in  the  ar- 
teries and  smaller  blood  vessels  giving  rise  to  various  symptoms, 
is  a  theory  for  which  there  is  no  proof. 

According  to  Virchow,^  urine  rich  in  uric  acid  causes  inflamma- 
tion of  the  bladder.     This  has  not  been  confirmed. 

Structural  Changes  Due  to  Putin  Bodies 

EFFECT  OF  PURIN  BASES 

According  to  Gaucher,^  injection  of  xanthin  and  paraxanthin 
into  guinea  pigs  for  a  few  weeks  caused  kidney  lesions  similar 
to  those  found  after  mercury  and  lead  poisoning.  Kolisch  ® 
found  similar  lesions  in  rabbits  after  injection  of  hypoxanthin 
for  a  month.  Croftan  ^^  gave  small  injections  of  xanthin  and 
hypoxanthin  to  rabbits  for  a  long  period,  and  found    granular 

1  W.  Filehne.  Ueber  einige  Wirkungen  des  Xanthins.  Arch,  fiir  Anat.  u.  Physiol. ,  72 
(1886). 

^  O.  Schmiedeberg.  Vergleichende  Untersuchungen  iiber  die  pharmakologischen 
Wirkimg  einier  Purinderivate.     Ber.  der  Dtsch.  chem.  Gesell.,  34,  2550  (1901). 

3  A.  Croftan.  An  Investigation  into  the  Cause  of  So-called  Uric  Acid  Lesions  and 
Rational  Therapeutics  of  the  Uratic  Diathesis.     N.  Y.  Med.  Journ.,  72,  221  (1900). 

*  M.  Stadthagen.  Ueber  das  Vorkommen  der  Harnsaure  in  verschiedenen  tierischen 
Organen,  ihr  Verhalten  bei  Leukaroie,  und  die  Frage  ihrer  Entstehung  aus  den  Stiok- 
stoffbasen.     Virchow's  Archiv,  109,  390  (1887). 

5  T.  Hall.     The  Purin  Bodies  of  Foodstuffs.     Manchester,  Eng.  (1902). 

6  A.  Haig.     Uric  Acid  as  a  Factor  in  the  Cause  of  Disease.     3d  ed.,  Phila.  (1896). 

^  R.  Virchow.     Ueber  Nephritis  arthritica.     Berl.  klin.  Woehenschrift,  21,  1  (1884). 

*  Gaucher.  Pathog^'niede  nephrite.  Th^se,  Paris  (1886),  and  Recherches  exp^riment- 
elles  sur  la  pathogenie  des  nephritis  par  auto-intoxication.     R^vue  de  Med.,  8,  885  (1888). 

9  R.  Kolisch.    Ueber  Wesen  und  Behandlung  der  uratischen  Diathese.    Stuttgart  (1895). 

1"  A.  Croftan.  An  Investigation  into  the  Cause  of  So-called  Uric  Acid  Lesions  and 
Rational  Therapeutics  of  the  Uratic  Diathesis.     N.  Y.  Med.  Journ.,    72,  221    (1900),  also 

Ibid.  Role  of  Alloxuric  Bases  in  the  Production  of  the  Cardio-Vascular  Changes  of 
Nephritis.     Am.  Journ.  of  Med.  Sciences,  120,  592  (1900). 


Pathology  261 

degeneration  of  the  epithelial  cells  lining  the  tubuli  contorti,  a 
proliferation  of  the  endothelium  of  the  intertubular  capillaries, 
and  albumin  in  the  urine.  Hall  ^  found  degenerative  changes 
in  the  kidneys  and  liver  of  rabbits  after  small  daily  doses  of  hypo- 
xanthin  and  guanin  for  fifty  days.  The  results  may  not,  how- 
ever, be  the  same  in  man  as  in  rabbits. 

Minkowski  ^  observed  that  adenin  feeding  brought  about  patho- 
logical changes  in  the  kidneys  of  rabbits.  His  statement  that 
the  adenin  causes  the  formation  of  uric  acid  concretions  in  the 
kidney  is  probably  erroneous.  In  rats,  Nicolaier  ^  found  similar 
concretions  in  the  kidneys  after  adenin  feeding,  but  these  concre- 
tions consisted  of  6-amino-2-8-dioxypurin,  an  oxidation  product 
of  adenin.  According  to  Hager,*  Carbone  and  Generali  found 
that  injections  of  adenin  hydrochloride  cause  necrosis  and  in- 
flammation. Hager  does  not  give  details  concerning  the  kind  of 
animal  used  and  the  place  of  inflammation. 

EFFECT   OF   URIC   ACID 
In  Birds 

Physiologists  have  never  been  able  to  agree  in  their  views 
concerning  the  effect  of  uric  acid  on  the  organism.  To  this  fact 
is  due  in  part  the  number  of  different  theories  of  gout.  The 
question  has  been  studied  experimentally  in  a  number  of  different 
ways. 

Ebstein  ^  found  after  injection  of  potassium  chromate  into 
cocks  that  concretions  of  sodium  urate  appear  in  the  kidneys. 
According  to  Ebstein,  the  tissue  was  found  to  be  necrosed  at  all 

1 1.  Hall.  Metabolism  in  Gout  and  the  Need  for  Combined  Investigation.  Practi- 
tioner, 71,  61  (1903). 

Ihid.  Beitrage  zur  Kenntniss  der  Wirkung  der  Purinsubstanzen.  Virchow's  Archiv, 
174,  359  (1903). 

^  *i~_MJ£]^™2Mi-T  Untersuchungen  zur  Physiologie  und  Pathologie  der  Harnsaure  bei 
Saugetliieren.     Arch,  fiir  exp.  Path.  u.  Pharm.,  41,  375  (1898),  also 

Ihid.  Ueber  Stoffwechselprodukte  nach  Thymusfutterung.  Centralblatt  fiir  innere 
Medizin,  19,"500  (1898). 

^W.  Nicolaier.  Ueber  die  Umwandlung  des  Adenins  im  thierischen  Organismus. 
Zeitschr.  fur  klin.  Medizin,  45,  359  (1902). 

*  Carbone  and  Generali.  July  Meeting  of  the  Turin  Medical  Academy,  according  to 
O.  Hager.     Zur  Pathogenic  der  Gicht.     Miinchen.  med.  Wochenschrift,  47,  1101  (1900). 

s  W.  Ebstein.  Ueber  den  gichtischen  Prozess.  Verhandl.  des  2t  Kongr.  fiir  innere 
Medizin  (1882),  p.  79,  also 

Ihid.  The  Regimen  to  be  Adopted  in  Cases  of  Gout.  Transl.  by  Scott.  London 
(1885),  and 

Ihid.     La  goutte,  sa  nature  et  .son  traitement.     Transl.  by  E.  Chambard.    Paris  (1SS7). 


262      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

places  where  the  concretions  appeared.  In  many  places  the 
necrosed  patches  extended  beyond  the  limits  of  the  concretions. 
On  account  of  these  facts /Ebstein  came  to  the  conclusion  that 
the  necrosis  precedes  the  formation  of  the  concretions,  and  is 
caused  by  the  urates  in  solution.  A  free  acid  is  generated  by 
the  necrosed  tissue,  and  this  acid  causes  precipitation  of  the  acid 
urate,  according  to  this  author.  He  stated  further  that  in  gout 
there  is  a  necrosis  where  the  concretions  are  found,  and  that 
this  necrosis  is  of  the  same  character  as  that  found  in  the  kidneys 
of  birds  after  chromate  injections. 

Schreiber  and  Zaudy  ^  repeated  the  work  of  Ebstein,  and  came 
to  the  conclusion,  in  agreement  with  this  author,  that  tissue 
necrosis  precedes  the  deposition  of  the  urates.  Ebstein  still 
maintained  this  vein  in  a  recent  article.^ 

V.  Kossa  ^  states  that  oxalic  acid,  phenol,  cane  sugar,  dextrose, 
and  other  substances,  as  well  as  potassium  chromate,  cause 
necrosis  and  formation  of  urate  concretions  in  the  kidney,  liver, 
spleen,  peritoneum,  and  in  other  parts  of  birds.  Kionka  *  brought 
about  a  gouty  condition  in  hens  by  feeding  them  exclusively  on 
meat  for  a  long  period.  He  states  that  the  condition  brought 
about  is  the  same  as  that  obtained  by  Ebstein  after  potassium 
chromate  injections.  Neither  Kionka  nor  von  Kossa  investigated 
the  tissue  changes  very  carefully,  nor  did  they  search  for  urates 
in  unchanged  tissue.  Their  results,  therefore,  cannot  be  taken 
as  confirmation  of  Ebstein 's  view  that  urates  deposit  only  in 
necrosed,  dead  tissue. 

Likhatscheff  ,^  on  the  other  hand,  who  brought  about  the  depo- 
sition of  urates  in  hens  by  tying  the  ureters,  found  urates  deposited 

1  E.  Schreiber  und  Zaudy.  Ueber  die  bei  Vogeln  kiinstlich  zu  erzeugenden  Harn- 
saureablagerungen.     Pfliiger's  Archiv,  79,  53  (1900). 

2  W.  Ebstein.  Gicht.  In  Ebstein  und  Schwalbe's  Handbuch  der  praktischen  Medizin. 
Bd.  Ill,  Th.  2  (1901),  Stuttgart. 

*J.   von  Kossa.     Kiinstlich  Erzeugung  der  Gicht  durch  Gifte.     Arch,     internat.   de 
Pharmacodjmamie,  5,  97  (1898),  also 
^  Ibid.     Beitrag  zur  Wirkung  der  Zuckerarten.     Pfliiger's  Archiv,  75,  310  (1899). 

*  H.  Kionka._  Zur  Kenntniss  des  Stoffwechsels  fleischgefiitterter  Htihner.  Arch,  ftir 
Pharmacodynamie,  7,   55   (1900),   also 

Ibid.  Entstehung  und  Wesen  der  "  Vogelgicht  "  und  ihre  Beziehung  zur  Arthritis  urica 
desMenschen.     Arch,  fiir  exp.  Path.  u.  Pharm.,  44,  186  (1900),  also 

Ibid.  Einfluss  des  Kalkes  auf  das  physiologische  Verhalten  gichtkranker  Hiihner. 
Arch,  fiir  exp.  Path.  u.  Pharm.,  44,  207  (1900). 

5  A.  Likhatscheff.  Experimentelle  Untersuchungen  iiber  die  Folgen  der  Ureterunter- 
bindung  bei  Huhnern  mit  besonderer  Beriicksichtigung  der  nachfolgenden  Uratablage- 
rung.  Ziegler's  Beitrage  zur  pathologischen  Anatomie  und  allgemein  Pathologie,  20,  102 
(1896). 


Pathology  263 

in  healthy  tissue.  This  discovery  has  been  confirmed  l^y  Freud- 
weiler.^ 

Riehl  ^  likewise  found  urates  in  unchanged,  healthy  tissue. 
According  to  this  author,  Ebstein's  results  are  due  to  his  manner 
of  preparing  sections  for  examination.  When  the  sections  are 
brought  into  water  a  little  of  the  urate  at  the  periphery  of  the 
concretions  dissolves.  This  leaves  a  slight  space  between  the 
urates  and  the  healthy  tissue.  It  was  this  space,  according  to 
Riehl,  that  led  Ebstein  to  believe  that  there  is  a  necrosis.  Riehl 
prepared  sections  for  examination  without  bringing  them  into 
contact  with  water,  and  found  that  the  urate  crystals  extend  into 
the  unchanged  tissue. 

Freudweiler  ^  caused  tissue  necrosis  in  birds  by  burning. 
He  then  tied  the  ureters  and  brought  about  the  deposition 
of  urates.  Urate  crystals  were  not  found  in  the  burned  tissue. 
Freudweiler  concluded  that  necrosed  tissue  does  not  attract 
urates. 

On  account  of  the  different  position  which  uric  acid  holds  in 
the  metabolism  of  birds  from  that  which  it  holds  in  mammals, 
we  cannot  draw  conclusions  concerning  gout  from  results  ob- 
tained by  artificially  disturbing  the  metabolism  of  uric  acid  in 
birds.  Further,  Freudweiler  ^  has  called  attention  to  the  fact  that 
in  gout  the  urates  are  found  chiefly  in  the  joints  and  cartilage  rather 
than  in  the  internal  organs,  and  that  in  birds  with  tied  ureters, 
or  suffering  from  chromate  poisoning,  the  urates  are  found  in 
the  internal  organs  and  in  the  serous  tissue,  while  the  joints  are 
generally  quite  free  from  urates.  Zaudy  ^  states  that  the  urates 
in  the  joints  of  birds  with  tied  ureters  are  found  only  on  the  sur- 
face of  the  cartilage,  while  in  gout  the  urates  are  found  in  the 
substance  of  the  articular  cartilage.  It  will  be  well  to  remember, 
however,  that  even  in  birds  necrosis  does  not  precede  the  deposi- 
tion of  urates,  when  for  any  reason  there  is  such  a  deposition  in 
the  tissues. 

1  M.  Freudweiler.  Experimentelle  Untersuchungen  iiber  die  Entstehung  der  Gicht- 
knoten.     Deutsche  Arch,  fur  klin.  Medizin,  6S,  155  (1900). 

2G.  Riehl.  Zur  Anatomie  der  Gicht.  Wien.  klin.  Wochenschrift,  10,  761  (1897), 
also 

Ibid.  Ueber  die  Anatomie  der  Gichtknoten.  Vortrag.  gehalten  in  der  Leipziger  medi- 
cinischer  Gesellschaft.,  9  Febr.,  1897;  Schmidt's  Jahrb.,  253,  271  (1897). 

3  Zaudy.  Bemerkungen  zur  der  Arbeit  von  His :  Schicksal  und  Wirkung  des  sauren 
harnsauren  Natrons  in  Bauch  und  Gelenkhohle  des  Kaninchens.  Deutsche  Arch,  fur  klin. 
Medizin,  67,  377  (1900). 


264      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

In  Mammals 

As  a  result  of  his  experiments  on  birds,  Ebstein  came  to  the 
conclusion  that  urates  in  solution  are  toxic,  and  attempted  to 
confirm  his  view  by  experiments  on  mammals.  He  found  that 
by  injection  of  a  solution  of  uric  acid  in  Na2HP04  into  the  cornea 
of  a  rabbit,  inflammation  and  obscurity  can  be  brought  about. 
With  Na2HP04  alone,  or  with  xanthin,  guanin,  creatin,  or  hippuric 
acid,  he  could  not  get  toxic  action.^  After  intravenous,  sub- 
cutaneous, and  intraperitoneal  injections  of  urate  into  rabbits, 
crystals  of  uric  acid  were  found  in  the  kidneys.^-  ^ 

Heidenhain  and  Neisser  ^  had  previously  observed  the  presence 
of  urate  crystals  in  the  kidneys  of  rabbits  after  intravenous 
injection  of  urates.  Freudweiler  *  injected  uric  acid  in  suspen- 
sion, and  also  sodium  acid  urate  solution  into  rabbits  and  into 
men,  and  concretions  of  uric  acid  were  obtained.  The  uric  acid 
and  urates  did  not  act  merely  like  a  foreign  body,  CaCOg  for 
example.  The  inflammation  came  on  sooner,  was  more  intense, 
and  lasted  longer  in  the  case  of  the  uric  acid  than  in  the  case  of 
CaCOg.  Uric  acid  and  sodium  acid  urate  are,  therefore,  toxic, 
according  to  this  author. 

His  ^  performed  experiments  similar  to  those  of  Freudweiler 
on  rabbits.  The  results  were  nearly  the  same.  His  concluded 
that  uric  acid  and  urates  act  partly  as  foreign  bodies  and  partly 
as  toxic  agents. 

According   to   Spiegelberg,**  subcutaneous   injection   of  urates 

1 W.  Ebstein.  Ueber  den  gichtischen  Prozess.  Verhandl.  des  2t  Kongr.  fur 
innere  Medizin,  79  (1882),  and 

Ibid.  The  Regimen  to  be  Adopted  in  Cases  of  Gout.  Transl.  by  J.  Scott.  London, 
1885,   and 

Ibid.  La  Goutte,  sa  nature  et  son  traitement.  Transl.  by  E.  Chambard.  Paris, 
1887,  also 

Ibid.     Beitrage  zur  Lehre  von  der  harnasuren  Diathese.     Wiesbaden  (1891). 

2  W.  Ebstein  und  A.  Nicolaier.  Ueber  die  Ausscheidung  der  Harnsaure  durch  die  Nieren. 
Virchow's  Archiv,   143,  337   (1896). 

3  R.  Heidenhain  und  A.  Neisser.  Versuohe  iiber  den  Vorgang  der  Harnabsonderung. 
Pfliiger's  Archiv,   9,    1    (1874). 

■'M.  Freudweiler.  E.xperimentelle  Untersuchungen  iiber  das  Wesen  der  Gichtknoten. 
Deutsche  Arch,  fiir  klin.  Medizin,  63,  266  (1899),  also 

Ibid.  Experimentelle  Untersuchungen  iiber  die  Entstehung  der  Gichtknoten.  Deutsche 
Arch,  fiir  klin.  Medizin,  68,  155  (1900). 

5  W.  His.  Das  Verhalten  der  Harnsaure  im  thierischen  Organismus.  Verhandl. 
des  17t  Kongr.  fiir  innere  Medizin  (1899),  315,  and 

Ibid.  Schicksal  und  Wirkungen  des  sauren  harnsauren  Natrons  in  Bauch-  und  Gelenk- 
hohle  des  Kaninchens.   Deutsche    Arch,    fiir  klin.   Medizin,  67,  81  (1900). 

"  H.  Spiegelberg.  Ueber  den  Harnsaureeinfarkt  der  Neugeborenen.  Arch,  fiir  exp. 
Path.  u.  Pharm.,  41,  428  (1898). 


Pathology  265 

causes  formation  of  concretions  only  in  young  rabbits,  not  in 
full-grown  ones. 

Croftan  ^  could  not  find  any  uric  acid  in  the  internal  organs 
after  injecting  it  into  rabbits.  According  to  Hager,^  Carbone 
and  Generali  did  not  succeed  in  obtaining  a  precipitation  of  urates 
by  the  injection  of  uric  acid  and  urates.  Hager  does  not  state 
what  kind  of  animal  was  used  in  the  experiments.  Ebstein  and 
Nicolaier  ^  fed  10  grams  uric  acid  per  day  to  a  dog  for  a  period  of 
five  months  and  a  half  without  obtaining  a  urate  deposit.  Croftan  * 
likewise  could  not  find  any  toxic  effect  or  any  changes  in  the  organs 
of  dogs  after  feeding  them  uric  acid,  as  well  as  injecting  it  into 
them  for  long  periods. 

Pfeiffer  ^  studied  the  subjective  symptoms  caused  by  uric  acid 
and  urates  in  man.  According  to  this  author,  after  the  injection 
of  a  sterile  solution  of  sodium  chloride  containing  uric  acid  in 
suspension,  pain  does  not  begin  until  from  twelve  to  twenty-four 
hours.  It  lasts  for  a  few  days.  If  doses  of  HCl  or  phosphoric 
acid  be  given  at  the  time  of  the  injection  and  for  a  little  time  before 
and  after,  either  there  is  no  pain,  or  it  does  not  begin  for  a  much 
longer  period.  If  alkalies  instead  of  acids  be  administered,  then, 
according  to  Pfeiffer,  the  pain  begins  very  soon  after  the  injection. 
A  solution  of  the  urate  causes  pain  almost  immediately  when 
injected. 

Pfeiffer  believes  that  his  experiments  indicate  that  the  soluble 
urate  only,  and  not  the  insoluble  uric  acid,  is  toxic.  The  uric  acid 
becomes  toxic  only  when  it  goes  into  solution  in  the  body.  The 
administration  of  acids  by  increasing  the  acidity  of  the  fluids  of  the 
body  prevents  the  solution  of  the  uric  acid.  The  administration 
of  alkalies,  on  the  other  hand,  hastens  the  solution  of  the  uric  acid. 

1  A.  Croftan.  Synopsis  of  Experiments  on  the  Transformation  of  Circulating  Uric 
Acid  in  the  Organism  of  Man  and  Animals.     Med.  Record,  64,  6  (1903). 

^  Carbone  and  Generali.  July  Meeting  of  the  Turin  Medical  Academy,  according  to  O. 
Hager.     Zur  Pathogenese  der  Gicht.     Miinchen  med.  Wochenschrift,  47,  1101  (1900). 

2  W.  Ebstein  und  A.  Nicolaier.  Ueber  die  Ausscheidung  der  Harnsaure  durch  die  Nieren. 
Virchow's  Archiv.    143,   337   (1896). 

■*  A.  Croftan.  An  Investigation  into  the  Cause  of  So-called  Uric  Acid  Lesions  and  a 
Rational  Therapeutics  of  the  Uratic  Diathesis.     N.  Y.  Med.  Journ.,  72,  221  (1900). 

5  E.  Pfeiffer.  Die  Natur  und  Behandlung  der  Gicht.  Verhandl.  des  8t  Kongr.  fiir  innere 
Medizin  (1889),  166,  also 

Ihid.     Die  Gicht  und  ihre  erfolgreich  Behandlung.     Wiesbaden  (1891),  2d  ed.,  also 

Ihid.  Ueber  Harnsaure  und  Gicht.  Berl.  klin.  Wochen.schrift,  Vol.  29,  pp.  383,  412, 
461,  490,  and  536  (1892),  also 

Ihid.  Ueber  die  Ausscheidung  im  Urin  wahrend  des  acuten  Gichtanfalles  mit  beson, 
derer  Beriicksichtigung  der  Harnsaure.     Berl.  klin.  Wochenschrift,  33,  319  (1S96). 


266      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

We  know,  of  course,  that  we  cannot  influence  directly  the 
reaction  of  the  fluids  of  the  body  in  the  manner  indicated  by 
Pfeiffer.  Furthermore,  His  ^  and  Freud weiler  ^  have  shown  that 
the  solution  of  the  urate  deposits  is  brought  about  by  the  vital 
action  of  the  phagocytes.  Freudweiler  ^  showed  that  acids  and 
alkalies  do  not  affect  the  rate  of  absorption,  and  Freudberg  ^ 
that  we  cannot  influence  the  reaction  of  the  blood  by  adminis- 
tration of  alkalies  or  acids. 

In  Pfeiffer 's  experiments,  his  judgment  may  have  been  biased 
by  the  fact  that  he  was  trying  to  prove  his  theory.  If  his  obser- 
vations were  correct,  his  explanations,  at  any  rate,  are  wrong. 

Mordhorst's  *  experiments  indicate  that  sodium  acid  urate  is 
not  toxic.  Uric  acid  dissolved  in  Na2HP04  does  not  affect  the 
eye  of  the  rabbit  any  more  than  Na2HP04  alone,  or  any  more 
even  than  common  drinking  water. 

According  to  Ebstein,'  concretions  of  urates  are  found  in 
gout  only  in  dead,  necrosed  tissue.  Occasionally  the  necrosed 
area  extends  beyond  the  urate  crystals,  but  the  urates  are  never 
found  in  healthy  tissue.  Bowlby,*'  too,  found  urates  deposited 
only  in  dead,  necrosed  tissue.  Von  Noorden  ^  and  Schreiber  * 
state  that  necrosis  precedes  deposition  of  urates  in  gout,  but  this 
seems  to  be  merely  an  expression  of  opinion.  They  do  not  offer 
any  experimental  proof  of  their  own. 

Pfeiffer  ^  states  that  uric  acid  and  sodium  acid  urate  do  not 
cause  necrosis  when  introduced  into  the  body.  He  believes  that 
in  gout  the  necrosis  precedes  the  deposition  of  the  urates. 

1 W.  His.  Das  Verhalten  der  Harnsaure  im  thierischen  Organismu?.  Verhandl.  des 
17t  Kongr.  fiir  innere  Medizin,  315  (1899),  also 

Ibid.  Schicksal  und  Wirkungen  des  sauren  harnsauren  Natrons  im  Bauch-  und  Gelenk- 
hohle  des  Kaninchens.     Deutsche  Arch,  fur  klin.  Medizin,  67,  81  (1900). 

2  M.  Freudweiler.  ExperimenteUe  Untersuchungen  iiber  die  Entstehung  der  Gieht- 
knoten.     Deutsche  Arch,  fur  klin.  Medizin,  68,  155  (1900),  also 

Ibid.     Deutsche  Arch,  fur  klin.  Medizin,  63,  266  (1899). 

3  Freudberg.  Ueber  den  Einfluss  von  Sauren  und  Alkalien  auf  die  Alkalescenz  des 
Blutes  und  die  Reaktion  des  Harnes.     Virchow's  Archiv,  125,  566  (1891). 

'•  Mordhorst.  Zur  Entstehung  der  Uratablagerung  bei  Gicht.  Virchow's  Archiv, 
148,  285  (1897). 

^  W.  Ebstein.    Beitrage  zur  Lehre  von  der  harnsauren  Diathese.    Wiesbaden  (1891), 'also 

Ibid.  Ueber  den  gichtischen  Process.  Verhandl.  des  2t  Kongr.  fur  innere  Medizin 
(1882),  79. 

6  A.  Bowlby.     Surgical  Pathology  and  Morbid  Anatomy,  p.  311,  London  (18S7). 

^  C.  von  Noorden.     Lehrbuch  der  Pathologie  des  Stoffwechsels.     Berlin  (1893). 

*  E.  Schreiber.  Ueber  die  Harnsaure  unter  physiologischen  und  pathologischen  Be- 
dingungen,   p.  102.     Stuttgart    (1899). 

8  E.  Pfeiffer.     Die  Gicht  und  ihre  erfolgreich  Behandlung.     Wiesbaden  (1891),  2d  ed. 


Pathology  267 

According  to  the  experiments  of  Freiichveiler  ^  and  His,^  on 
the  other  hand,  uric  acid  and  urates  are  slightly  toxic  and  cause 
a  necrosis.  His  confirmed  the  observation  of  Ebstein  that  necrosis 
is  sometimes  found  in  the  tissue  surrounding  the  concretions,  but 
considered  this  a  confirmation  of  his  own  view.  According  to 
His,  the  effect  on  the  surrounding  tissue  is  due  to  the  urate  in 
solution,  but  the  necrosis  is  secondary  to  the  formation  of  the 
deposit.  A  small  quantity  of  the  deposit  at  the  periphery  of  the 
concretions  goes  into  solution,  and  the  solution  exerts  a  slight 
toxic  action  on  the  surrounding  tissue. 

It  seems  to  be  fairly  well  settled  that  necrosis  does  not  neces- 
sarily precede  deposition  of  urates  in  gout.  Thus  Ranvier  ^  and 
Rindfleisch  *  found  gouty  cartilage  cells  normal  in  spite  of  the 
presence  of  urates.  Duckworth  ^  and  Luff "  found  gouty  con- 
cretions in  healthy  tissue.  Riehl,^  too,  found  urates  in  healthy 
tissue  in  gout.  He  attributes  Ebstein's  error  in  this  respect  to 
the  same  cause  as  in  his  experiments  on  birds.  When  the  section 
is  brought  into  contact  with  water,  the  urates  at  the  periphery 
of  the  crystal  mass  dissolve,  leaving  a  space  between  the  con- 
cretion and  the  tissue.  This  is  the  space  that  Ebstein  looked 
upon  as  necrosed.  Aschoff  ^  found  urates  deposited  in  the  kidney 
in  healthy  tissue.  Bennecke  ^  never  found  necrosis  extending 
beyond  the  crystalline  mass  of  urates.  Minkowski  ^°  has  repeated 
this  work  and  found  the  urate  concretions  in  healthy  tissue. 

According  to  Riehl,^  Freud weiler,^  and  His,^  the  tissue  change 

1  M.  Freudweiler.  Experimentelle  Untersuchungen  iiber  das  Wesen  der  Gichtknoten. 
Deutsche  Arch,  fiir  klin.  Medizin,  63,  266,  (1899),  also 

Ihid.  Experimentelle  Untersuchungen  iiber  die  Entstehung  der  Gichtknoten.  Deutsche 
Arch,  fiir  klin.  Medizin,  68,  155  (1900). 

2  W.  His.  Das  Verhalten  der  Harnsaure  im  thierischen  Organismus.  Verhandl.  des  17t 
Kongr.  fiir  innere  Medizin  (1899),  315,  also 

Ibid.  Schicksal  und  Wirkungen  des  sauren  harnsauren  Natrons  in  Bauch-  und  Gelenk- 
hohle  des  Kaninchens.     Deutsche  Arch,  fiir  klin.  Medizin,  67,  81  (1900). 

3  Ranvier.     Manuel  d'Histologie   pathologique   (1869). 

'  Rindfleisch.     Lehrbuch  der  pathologischen  Gewebelehre.     Leipzig  (1886). 

s  D.  Duckworth.     A  Treatise  on  Gout.     London  (1890). 

6  A.  Luff.  The  Chemistry  and  Pathologj'  of  Gout.  (Croonian  Lectures.)  Lancet  (1897), 
I,  857,  942,  and  1069. 

"  G.  Riehl.  Zur  Anatomie  der  Gicht.  Wien.  klin.  Wochenschrift,  10,  761  (1897), 
also,  Ueber  die  Anatomie  der  Gichtknoten.  Vortrag  gehalten  in  der  Leipziger  m^edizin, 
Gesellschaft,  9  Febr.  (1897),  Schmidt's  Jahrb.,  253,  271  (1897). 

*  L.  Aschofl.  Verhandl.  der  Deutsch.  patholog.  Gesellsch.  Miinchen,  I  (1899),  and 
II  (1900). 

'  E.  Bennecke.     Beitrage  zur  Anatomie  der  Gicht.     Arch,  fiir  klin.  Chir.,  66.  658  (1902). 

1"  O.  Minkowski.  Die  Gicht.  In  Nothnagel's  specielle  Pathologie  und  Therapie,  ^TI 
Band.  Ill  Theil,  p.  220  (1903). 


268      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

which  they  speak  of  as  a  necrosis  is  secondary  and  caused  by  the 
urate,  partly  by  its  action  as  a  foreign  body,  and  partly  by  its 
toxic  action. 

Litten  ^  did  not  believe  that  the  tissue  in  gout  is  really  necrosed. 
Minkowski,^  too,  states  that  the  tissue  surrounding  gouty  con- 
crements  is  not  really  necrosed.  It  does  not  stain  like  necrosed 
tissue. 

According  to  Beckart,^  the  anatomical  lesions  in  gout  are  not 
such  as  would  be  produced  by  an  acid,  but  look  rather  like  the 
slow,  degenerative  changes  that  occur  in  other  forms  of  disease. 
The  author  states  that  the  lesions  minus  the  urate  deposits. are 
described  by  Ziegler  *  as  the  constant  substratum  of  arthritis 
deformans. 

Mordhorst  ^  says  that  hyaline  degeneration  is  a  good  name 
for  the  lesion.  Necrosed  tissue  decomposes,  is  absorbed,  and 
replaced  by  cicatricial  tissue.  According  to  this  author,  in  the 
case  of  gout,  the  tissue  surrounding  the  urates  changes  to  a 
hyaline  mass.  Similarly,  in  the  guanin  gout  of  hogs,  there  is  no 
necrosis,  according  to  Mendelsohn,**  but  an  amjdoid  degeneration 
difficult  to  describe. 

It  can  be  seen  that  we  have  not  yet  a  perfectly  clear  under- 
standing of  the  interaction  of  tissue  and  urates.  It  seems  to  be 
certain  that  urates  can  deposit  in  healthy  tissues,  and  that  they 
cause  some  kind  of  change  which  is  probably  not  a  necrosis.  But 
it  may  also  be  true  that  a  slight  tissue  change  of  some  sort  pre- 
cedes the  deposition  of  the  urates,  and  that  when  a  crystal  is 
deposited  in  a  small  lesion  it  grows  by  accretion  and  extends  into 
healthy  tissue.  Experiments  have  not  yet  shown  that  this 
latter  possibility  can  be  excluded.     Likhatscheff  ^  has  suggested 

1  M.  I.itten.  Pathologisoh-anatomische  Beobachtungen.  Ein  Fall  von  schwerer  Gicht 
mit  Amyloiddegeneration.     Virchow's  Archiv,  66,  129  (1876). 

2  O.  Minkowski.  Die  Gicht.  In  Nothnagel's  Speeielle  Pathologie  und  Therapie  (1903) , 
VII  Band,  III  Theil,  p.  22.3  (1903). 

3  J.  Beckart.  On  the  Pathology  of  the  Gouty  Paroxysm.  Brit.  Med.  .Journ.,  1,  243 
(1895). 

*  E.  Ziegler.  Ueber  die  subchondralen  Veranderungen  der  Knochen  bei  Arthritis 
deformans  und  tiber  Knochencysten.     Virchow's  Archiv,  70,  502  (1877). 

5  Mordhorst.  Zur  Entstehung  der  Uratablagerungen  bei  Gicht.  Virchow's  Archiv, 
148,  285  (1897). 

6W.  Mendelsohn.  On  guanin  gout  in  the  hog,  and  its  relation  to  the  sodium  urate 
gout  of  man.     Am.  Journ.  of  Med.  Sciences,  N.  S.,  95,  109  (1888). 

'A.  Likhatscheff.  Experimen  telle  Untersuchungen  iiber  die  Frage  der  Ureteren  unter- 
bindung  bei  Huhnern  mit  besonderer  Beriicksichtigung  der  nachfolgenden  Uratablagerung, 
Ziegler's  Beitrage  zur  patholog.  Anatomie  und  allgem.   Pathologie,  20,   102  (1896). 


Laugier 

Wurzer 

16.7% 

20.0% 

16.7 

20.0 

16.7 

18.0 

8.3 

10.0 

16.7 

19.5 

2.2 

8.3 

10.3 

Pathology  269 

that  the  urates  do  not  cause  the  tissue  change  nor  the  tissue 
change  the  deposition  of  the  urates,  but  that  both  are  due  to  a 
common  cause. 

Gout 

Analysis  of  Concrements 

Lehmann,  Laugier,  and  Wurzer  give  the  following  analyses  of 
gouty  concretions :  ^ 

Lehmann 

Sodium  acid  urate 52.12% 

Uric  acid 

Calcium  acid  urate 1.25 

Soda 

Sodium  chloride  9.84 

Lime 

Calciuiu  phosphate 4.32 

Cellular  tissue  28.49 

Animal  matter    

Potassium  chloride    

Water 

Loss    16.6  

Water,  loss,  etc 3.98  

An  analysis  of  L'heritier  ^  shows: 

Urates  of  ammonia,  sodium,  and  lime 49.0% 

Phosphate  of  lime 42.0 

Organic  matter  and  water 9.0 

In  a  gouty  concretion  Marchand  found  :^ 

Sodium  acid  urate  34.20% 

Calcium  acid  urate 2.12 

Ammonium  carbonate    7.86 

Sodium  chloride 14.12 

Animal  matter   32.53 

Water 6.80 

Loss  2.37 

Two  analyses  of  Ebstein  and  Sprague  ^  show : 

Uric  acid  59.7%  61.27 

Animal  matter   27.88  26.45 

Na^O    9.3  12.28 

K2O    2.95 

CaO    17 

Mg,  Fe,  P^Os,  it  S trace 

1  Becquerel  and  Rodier.     Pathological  Chenii.-itry.     London    (1857),   515. 

2  R.  Marchand.     Lehrbuch  der  physiologischen  Chemie.     Berlin  (1844),  p.  107. 

3  W.  Ebstein  und  C.  Sprague.   Beitrage  zur  Analy.se  gichtischer  Tophi.   Virchow's  Archiv 
125,  207   (1891). 


270      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

In '  these  analyses  the  uric  acid  means  uric  acid  combined 
with  bases.  The  concretions  are  chiefly  sodium  acid  urate  and 
organic  matter. 

Uric  Acid  in  the  Blood 

Although  the  presence  of  uric  acid  in  gouty  blood  had  previ- 
ously been  suspected,  it  was  first  found  by  Garrod  in  1848.^  This 
author  was  able  to  demonstrate  by  the  so-called  thread  experi- 
ment that  uric  acid  is  always  present  in  the  blood  during  acute 
attacks  of  gout.  If  a  thread  which  has  been  dipped  in  blood  con- 
taining uric  acid  and  acidified  with  acetic  acid  be  allowed  to  dry, 
uric  acid  crystals  will  form  on  the  thread,  and  can  be  seen  under 
the  microscope.  According  to  Garrod,  uric  acid  likewise  is  found 
in  the  blood  in  chronic  gout,^^  but  not  in  the  intervals  between 
attacks  in  acute  gout.  He  did  not  find  uric  acid  in  the  blood  in 
health. 

Jones ,^  Ranke,*  Charcot,^  Cantani,"  and  Salomon  ^  confirmed  the 
discovery  of  uric  acid  in  the  blood  either  by  the  thread  experi- 
ment or  by  precipitation  with  acid.  Abeles  *  and  Strauss  ® 
found  uric  acid  in  gouty  blood  by  the  murexid  test.  Klemperer  ^^ 
found  from  .07  to  .09  gram  uric  acid  in  1,000  cc.  of  blood  taken 
during  an  acute  attack  of  gout.  According  to  Magnus-Levy," 
there  is  as  much  uric  acid  in  gouty  blood  between  attacks  as 
during  acute  attacks. 

Gairdner  ^^  and  Meldon  ^^  have  each  reported  a  case  where  uric 

1  A.  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheumatism,  and  Bright's  Disease.     Medioo-Chirurgioal  Trans.,  31,  83  (1848). 

2  Ihid.     The  Nature  and  Treatment  of  Gout  and  Rheumatic  Gout.     London  (1859). 
■*  H.  Jones.     A  Treatise  of  Gravel,  Calculus,  and  Gout. 

*  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidung  der  Harnsaure  beim 
Menschen.    Miinchen  (1858). 

5  Charcot.  Du  rheumatisme  nouex  et  de  la  goutte.  Gazette  des  hopiteaux,  1866  and 
1867. 

6  A.  Cantani.  Oxalurie,  Gicht,  und  Steinkrankheiten.  Specielle  Pathologie  und 
Therapie  der  Stoffwechselkrankheiten.     German  translation  by  H.  Hahn  (1880). 

'  G.  Salomon.  Ueber  pathologisch-chemische  Blutuntersuchungen.  Charite  Annalen, 
5,   137   (1880). 

8  M.  Abeles.  Ueber  Hainsaure  im  Blute  und  einigen  Organen  und  Geweben.  Wien.  med. 
Jahrb.,  83,  497  (1887). 

^  H.  Strauss.  Die  chronischen  Nierenentztindungen  und  ihre  Einwirkungen  auf  die 
Blutflussigkeit.     Berlin    (1902). 

1"  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Vortrag.  geh.  in  der  Verein 
fur  innere  Med.  zu  Berlin,   1895.     Deutsche  med.  Wochenschrift,  21,  655  (1895). 

11  A.  Magnus-Levy.  Harnsauregehalt  und  Alkalescenz  des  Blutes  in  der  Gicht.  Ver- 
handl.  des  16t  Kongr.  fiir  innere  Medizin  (1898),  266,  also 

Ihid.     Ueber  Gicht.     Zeitschr.  fur  klin.  Med.,  36,  412  (1898). 

'2  W.  Gairdner.     On  Gout,  its  History,  its  Causes,  and  its  Cure.  4th  ed.  London  (1860). 

13  A.  Meldon.     Pathology  and  Treatment  of  Gout.     Brit.  Med.  Journ.  (1881),  I,  466. 


Pathology  271 

acid  was  found  in  healthy  blood.  They  did  not  state  their  method 
of  analysis.  Weintraud  ^  found  uric  acid  in  the  blood  of  a  healthy 
man  after  a  meal  of  thymus.  Croftan  ^  states  that  he  found  .02 
to  .03  gram  uric  acid  in  a  hundred  grams  of  blood.  This  is  more 
than  any  author  has  reported,  even  in  gouty  blood,  and  is  more 
than  Roberts  ^  found  can  be  dissolved  in  the  blood.  Croftan 
analyzed  the  serum  plus  the  blood  corpuscles,  however,  and  as 
he  does  not  state  his  method  of  analysis,  it  seems  possible 
that  the  purin  bases  in  the  corpuscles  may  have  come  into  the 
analysis. 

Neither  von  Jaksch,'*  Bain,''  nor  Klemperer  **  could  find  uric 
acid  in  any  of  the  healthy  blood  which  they  examined. 

Uric  acid  has  been  found  in  the  blood  in  diseases  other  than 
gout.  Garrod  '^  found  uric  acid  in  the  blood  by  the  thread  ex- 
periment in  acute  rheumatism,  albuminuria,  and  chronic  lead 
poisoning.  Salomon  *  found  it  in  the  blood  in  pneumonia, 
anemia,  and  phthisis.  According  to  Haig,^  uric  acid  is  found  in 
the  blood  in  pneumonia  and  certain  other  diseases.  Haig  used 
the  Haycraft  method  of  analysis,  however,  and  this  method  gives 
the  purin  bases  as  well  as  uric  acid.  Von  Jaksch  '"  found  uric  acid 
in  the  blood  in  nephritis,  lead  poisoning,  malaria,  typhus,  liver 
carcinoma,  intestinal  inflammation,  anemia,  and  pneumonia, 
and  in  conditions  of  emphysema  and  dyspnea  occasionally. 
Magnus-Lev3^'s  experiments  show  the  presence  of  uric  acid  in 

1  W.  Weintraud.  Ueber  Harnsaure  im  Blute  unci  ihre  Bedeutung  fiir  die  Entstehung 
der  Gicht.     Wien.  klin.  Rundschau,  10,  p.  3  and  21  (1896). 

2  A.  Croftan.  An  Investigation  into  the  Causes  of  So-called  Uric  Acid  Lesions  and  a 
Rational  Therapeutics  of  the  Uratic  Diathesis  N.  Y.  Med.  Journ.,  72,  221  (1900). 

3  W.  Roberts.  On  the  Chemistry  and  Therapeutics  of  Uric  Acid,  Gravel,  and  Gout. 
(Croonian  Lectures  for  1892.)     Lancet,  I,  1345  and  1399,  and  IL  69,  127  (1892). 

*  von  Jaksch.  Ueber  die  klinische  Bedeutung  des  Vorkommens  von  Harnsaure  und 
Xanthinbasen  im  Blute,  den  Exudaten  und  Transudaten.  Zeitschr.  fiir  Heilk.,  11,  41.5 
(1890). 

5  W.  Bain.  An  Experimental  Contribution  to  the  Study  of  Gout.  Brit.  Med.  .lourn. 
(1899),  II,  1164. 

^  G.  Klemperer.  Zur  Pathologic  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
.schrift,  21,  655  (1895). 

'  A.  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheumatism,  and  Bright's  Disease.  Medico-Legal  Transactions,  31,  83  (1848), 
also 

Ihid.     The  Nature  and  Treatment  of  Gout  and  Rheumatic  Gout.     London  (1848). 

*  G.  Salomon.  Ueber  die  Verbreitung  und  Entstehung  von  Hypoxanthin  und  Milch- 
saure  im  thierischen  Organismus.     Zeitschr.  fiir  physiol.  Chem.,  2,  65  (1878). 

8  A.  Haig.     LMc  Acid  as  a  Factor  in  the  Cause  of  Disease.     3d  ed.     Phila.  (1896). 

1°  R.  von  Jaksch.  L'eber  tiricacidaemie.  Deutsche  med.  Wochenschrift,  16,  741 
(1890),  also  Ueber  die  klinische  Bedeutung  des  Vorkommens  von  Harnsaure  und  Xan- 
thinbasen im  Blute,  den  Exudaten  und  Transudaten.     Zeitschr.  fiir  Heilk..  11,  415  (1890). 


272      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

the  blood  in  various  kidney  diseases,  lead  colic,  pneumonia, 
phthisis,  arteriosclerosis,  bronchitis,  and  emphysema  ^  and  in 
leukemia.^  Klemperer  ^  has  found  about  .  1  gram  uric  acid  in 
1,000  cc.  of  leukemic  blood,  and  even  a  larger  quantity  in  the 
blood  in  a  patient  with  nephritis.  This  is  more  than  he  found  in 
the  blood  of  his  gouty  patients.  Petren  *  found  uric  acid  in  the 
blood  in  pneumonia,  hysterical  vomiting,  and  gonorrheal  rheu- 
matism. In  cases  of  Bright 's  disease,  malignant  disease,  aneur- 
ism of  the  aorta,  ulcerative  endocarditis,  and  pneumonia,  Watson^ 
found  uric  acid  in  the  blood  after  death. 

Wolf "  and  Tichborne  ^  state  that  they  found  uric  acid  in  the 
perspiration  of  gouty  patients.  Lecorche,*  Lehmann,^  Garrod,^" 
and  Magnus-Levy  ^  could  not  confirm  this  discovery. 

We  can  say,  then,  that  uric  acid  is  found  in  the  blood  in  gout 
and  in  a  few  other  diseases,  but  probably  not  generally  in  health. 

Alkalinity  of  the   Blood   in  Gout 

An  assumption  upon  which  many  authors  have  based  their 
theories  of  gout  is  that  the  alkalinity  of  the  blood  is  decreased  in 
this  disease.  This  assumption  has  never  been  found  true  experi- 
mentally, even  by  inaccurate  methods  of  analysis.  The  alkalinity 
of  the  blood  in  gout  has  never  been  determined  by  an  accurate 
method,  that  is,  by  a  method  which  gives  the  "  actual  "  con- 
centration of  the  hydroxyl  ions.  It  is  extremely  doubtful  that 
a  decrease  in  the  real  alkalinity  would  be  found.  The  normal 
alkalinity  of  the  blood  is  so  extremely  small  that  it  would  need 
but  a  slight  decrease  in  the  concentration  of  the  hydroxyl  ions 
to  make  the  blood  neutral  or  even  acid. 

1  A.  Magnus-Levy.     Ueber  Gicht.     Zeitschr.  fiir  klin.  Med.,  36,  412  (1898). 

2  Ibid.  Ueber  den  Stoffwechsel  bei  acuter  und  chronischer  Leukamie.  Virchow's 
Archiv,  152,  107  (1895). 

3  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
schrift,  21,   655    (1895). 

*  K.  Petren.  Ueber  das  Vorkommen  von  Harnsaure  im  Blute  bei  Menschen  und  Sauge- 
thieren.     Arch,  fiir  exp.  Path.  u.  Pharm.,  41,  265  (1898). 

5  C.  Watson.  Observations  on  General  Metabolism  and  the  Blood  in  Gout.  Brit. 
Med.  Journ.,  .110   (1900). 

6  Wolf.     Diss.   sist.   casum.     Calculositats.     Tubingen,   1817. 

7  C.  Tichborne.  On  the  Elimination  of  Uric  Acid  by  the  Skin,  and  the  Difificulty  of 
Detecting  Minute  Quantities  of  that  Acid.     Brit.  Med.  Journ.  (1887),  II,  1097. 

8  Lecorch^.     Traitd   de   la   Goutte.    Paris    (1884). 
^  Lehmann.     Physiol.  Chem.  (1855). 

i°A.  Garrod.  On  the  Blood  and  Effused  Fluids  in  Gout,  Rheumatism,  and  Bright 's 
Disease.     Medico-Legal  Transactions,  .37,  49  (1854). 


Pathology  273 

Drouin/  Liiff,^  Strauss,^  Watson/  and  Magnus- Levy/'  who 
used  titration  methods,  did  not  find  the  blood  alkalinity  decreased, 
nor  did  Klemperer,^  who  took  the  content  of  CO2  as  a  measure  of 
the  blood  alkalinity.  A  tendency  toward  decreased  alkalinity 
of  the  blood  is  sometimes  accompanied  by  increased  ammonia 
in  the  urine.  Neither  Magnus-Levy  ^  nor  Vogel  ^  could  find  in- 
creased ammonia  in  the  urine  in  gout.  Soetbeer  **  found  less 
ammonia  in  the  urine  of  gouty  patients  living  on  the  same  diet 
than  in  that  of  normal  patients. 

Only  Pfeiffer  ^  and  Aronsohn  ^^  have  assumed  that  the  alkalinity 
of  the  blood  is  increased  in  gout.  We  have  seen  that  they  have 
offered  no  direct  evidence  in  favor  of  this  view,  and  the  only 
indirect  evidence  they  have  offered  is  exceedingly  bad. 


Solubility  of  Uric  Acid  in  the  Blood  and  Tissues 

We  have  already  stated  that  Roberts  "  found  that  the  pres- 
ence of  sodium  salts  decreases  the  solubility  of  sodium  acid  urate 
solution.  He  found  that  a  solution  of  one  part  sodium  acid  urate 
in  6,000  of  blood  serum  is  saturated.  Klemperer  ^^  found  .17  gram 
uric  acid  soluble  in  100  cc.  of  blood  serum.     It  seems  probable 

1  R.  Droiiin.     Hemoalkalim^trie.  Paris,  1892. 

2  A.  Luff.     The  Alkalinity  of  the  Blood  in  Gout.     Brit.  Med.  Journ.,  1,  1066  (1898),  and 
Ihid.     Gout:     Its  Pathology  and  Treatment.     New  York  (1899). 

5  H.  Strauss.  Ueber  das  Verhalten  der  Blutalkalescenz  des  Menschen  unter  einigen 
physiologischen  und  pathologischen  Bedingungen.  Zeitschr.  fiir  klin.  Med.,  30,  317 
(1896). 

^  C.  Watson.  Observations  on  General  Metabolism  and  the  Blood  in  Gout.  Brit. 
Med.  Journ.,  1,  10  (1900). 

5  A.  Magnus-Levy.     Ueber  Gicht.     Zeitschr.  fiir  klin.  Med.,  36,  412  (1898). 

8  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
schrift,  21,   665   (1895). 

^  L.  Vogel.  Ueber  den  Stoffwechsel  bei  Gichtkranken.  Enthalten  in  einem  Vortrag 
von  Noorden's  Beitrage  zur  Emahrungenslehre  nach  Versuchen  von  Dr.  Kayser,  Krug, 
Dapper,  u.  Vogel.  Sitzungsber.  der  physiol.  Gesellsch.,  Berl.,  17  Febr.,  1893,  and  Du 
Bois  Archiv,  377  (1893),  also 

Ihid.  Ueber  Gicht,  in  von  Noorden's  Beitrage  zur  Lehre  vom  Stoflwechsel.  Berl.  (1894), 
H.  2,  p.  113. 

*  F.  Soetbeer.  Ein  Stoffwechselversuch  bei  Gicht.  Zeitschr.  fiir  physiol.  Chem.,  40, 
55   (1903). 

^  E.   Pfeiffer.     Die  Gicht  und  ihre  erfolgreich  Behandlung.     Wiesbaden  (1891),  2d  ed. 

1"  E.  Aronsohn.  Zur  Natur  und  Behandlung  der  Gicht  und  iiber  die  Bedeutung  der 
Emser  Wilhelmsquelle.     Deutsche  med.  Wochenschrift,  16,  381  (1890). 

'1  W.  Roberts.  On  the  Chemistry  and  Therapeutics  of  Uric  Acid,  Gravel,  and  Gout. 
(Croonian  Lectures  for  1892.)     Lancet  (1892),  I,  1345  and  1399,  and  II,  69  and  127. 

12  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
schrift, 21,  655  (1895),  and 

Ihid.     LTntersuchungen  iiber  Gicht  und  harnsiiuren  Nierensteine.     Berhn  (1896). 


274      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

that  Klemperer's  figures  for  the  sohibility  of  uric  acid  in  blood 
serum  are  rather  high,  unless  we  assume  that  the  uric  acid  com- 
bines organically  with  some  compound  in  the  blood.  Sodium  acid 
urate  is  soluble  only  in  1,100  to  1,200  parts  of  water  at  the  room 
temperature.  Klemperer's  results  would  indicate  that  this  salt  is 
soluble  in  about  600  parts  of  blood  serum,  whereas  we  should 
expect  it  to  be  rather  less  soluble  in  blood  serum  than  in  water. 

According  to  Klemperer,  gouty  blood  is  not  nearly  saturated 
with  uric  acid.  The  amount  of  uric  acid  in  gouty  blood  is  so 
small  in  comparison  with  its  solubility  that  such  blood  can  dis- 
solve practically  the  same  quantity  of  uric  acid  as  normal  blood 
free  from  uric  acid. 

Luff  ^  has  shown  that  sodium  acid  urate  is  not  less  soluble  in 
blood  serum  which  has  been  one  fourth,  one  half,  or  even  three 
fourths  neutralized  with  hydrochloric  acid  or  tartaric  acid.  In 
fact,  the  urate  seems  to  be  even  slightly  more  soluble  in  the  less 
alkaline  serum.  This  author  found  that  meat  ash  decreases  the 
solubility  of  the  urate  in  blood  serum,  but  that  vegetable  ash 
does  not.  He  studied  the  chemistry  of  these  ashes  and  made 
experiments  with  pure  salts  and  mixtures  of  salts,  but  could  not 
determine  the  reason  for  the  difference  in  action  of  the  ashes. 

It  is  plain  that  those  theories  which  assume  that  the  alka- 
linity of  the  blood  is  decreased  in  gout,  or  that  the  blood  is 
saturated  with  uric  acid,  and  that  on  this  account  uric  acid  pre- 
cipitates out,  are  based  on  erroneous  notions. 

It  will  be  remembered  that  Goto  and  Minkowski  had  expressed 
the  view  that  uric  acid  might  exist  in  the^body  in  combination 
with  thymic  acid  or  nucleic  acid.  Schmoll  ^  has  suggested  the 
possibility  that  uric  acid  normally  circulates  in  the  blood  in  com- 
bination with  thymic  acid,  and  that  in  gout  it  is  free  and  not 
combined  with  thymic  acid.  He  supposes  that  in  health  uric  acid 
is  formed  only  by  oxidation  from  the  nucleoproteids,  and  that 
thymic  acid  is  always  formed  at  the  same  time  to  combine  with  it, 
but  that  in  gout  uric  acid  is  formed  by  synthesis  and  that  no  thy- 
mic acid  is  formed  at  the  same  time.  The  evidence  he  offers  in 
support  of  his  theory  is  the  slight  increase  in  the  excretion  of  uric 

1  A.  Luff.  The  Chemistry  and  Pathology  of  Gout.  (Goulstonian  Lectures.)  Lancet 
(1897),  I,  857,  942,  and  1069,  and  Gout,  Its  Pathology  and  Treatment.  New  York 
(1899). 

^E.  SchnioU.  Sur  la  formation  de  I'acide  urique  dans  la  goutte  at  les  causes  de  sa 
precipitation  dans  les  tissus.     Arch.  g^n.  de  med.,   2,  2433    (1904). 


Pathology  275 

acid  that  he  sometimes  found  after  use  of  thymic  acid,  and  the 
fact  that,  according  to  him,  the  uric  acid  excretion  can  be  increased 
by  adding  casein  to  the  food,  a  fact  which  led  him  to  believe  that 
uric  acid  can  be  formed  by  synthesis  in  the  body. 

In  regard  to  the  synthesis  of  uric  acid,  it  will  be  remembered 
that  we  have  a  mass  of  evidence  to  oppose  Schmoll's  view.  The 
increased  excretion  of  uric  acid  after  thymic  acid  feeding  was 
only  slight  and  not  present  in  all  cases.  In  regard  to  thymic  acid, 
we  know  that  the  general  opinion  is  that  nucleic  acid  cannot  be 
further  decomposed  into  a  definite  body  (thymic  acid)  free  from 
purin  bases.  We  have  also  the  experiments  of  Schittenhelm  and 
Bendix,^  which  would  seem  to  indicate  that  nucleic  acid  does  not 
act  as  a  solvent  for  uric  acid  in  the  organism. 

Metabolism  in  Gout 
METABOLISM  OF  URIC  ACID 

Garrod,^  who  used  the  inaccurate  Heinz  method  of  analysis, 
found  the  excretion  of  uric  acid  diminished  in  gout.  This  is  one 
of  the  points  on  which  he  based  his  theory  of  this  disease.  Other 
experimenters  who  used  the  Heinz  method,  among  whom  were 
Bocker,^  Lehmann,*  Ranke,'^  Braun,''  Bartels,^  Cantani,^  and 
Lecorche  '^  confirmed  Garrod.  Bouchard  ^°  found  the  excretion 
of  uric  acid  low  ^°  except  in  the  first  few  days  ^^  of  an  acute 
attack.  Fawcett  ^^  found  the  excretion  of  uric  acid  just  a  little 
low  in  gout. 

1  A.  Schittenhelm  und  E.  Bendix.  Ueber  das  Schicksal  der  m  die  Blutbahn  ein- 
gebrachten   Nukleinsaure,   30,    1164   (1904). 

2  A.  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheumatism,  and  Bright's  Disease.     Medico-Chirurg.  Trans.,   31,  83   (1848),  also 

Ibid.     The  Nature  and  Treatment  of  Gout  and  Rheumatic  Gout.     London,  1859. 

3  Booker.  Ziu-  Pathologie  der  Gicht.  Rhein.  Monatsh.,  Feb.  (1850),  and  Canstatt's 
Jahresber.  (1850),  158. 

'^  Lehmann.     Lehrbuch  der  physiol.  Chem.,  Vol.  II  (1853). 

5  Ranke.  Beobachtungen  und  Versuche  iiber  die  Ausscheidung  der  Harnsaure  beim 
Menschen.     Munchen  (1858). 

^  Braun.     Beitrage  zu  einer  Monographic  der  Gicht.     Wiesbaden  (1860). 

''Bartels.  Untersuchungen  iiber  die  Ursachen  einer  gesteigerten  Ausscheidung  der 
Harnsaure  in  Krankheiten.     Deutsche  Arch,  fiir  klin.  Medizin,  I,  13  (1866). 

*  Cantani.  Specielle  Pathologie  und  Therapie  der  Stoffwechselkrankheiten.  German 
translation  by  Hahn  (1880),  Bd.  II. 

"Lecorche.     Traite  theorique  et  practique  de  la  goute.     Paris  (1884). 

'"C.  Bouchard.  Lemons  sur  les  maladies  par  ralentissement  de  la  nutrition.  3  ed.  Paris 
(1890). 

^^  Ibid.     Maladies  par  ralent issement  de  la  nutrition.     Paris  (1882). 

'- J.  Fawcett.  On  the  L'rinary  Excretion  in  Gout  and  the  Effect  of  Treatment  with 
Colchicum  and  Salicylate  of  Soda.     Guy's  Hospital  Reports,  52,  115  (1895). 


276     The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

The  authors  who  have  used  an  accurate  method  for  determin- 
ing uric  acid,  Levison/  Schmoll,^  Camerer/  Badt/  Klemperer,^ 
Martin,*'  Zagari/,  and  Bain,^  could  not  find  that  the  excretion 
of  uric  acid  is  decreased  in  gout.  Kaufmann  and  Mohr"  and 
Grossman  ^^  have  found  the  exogenous  uric  acid  in  gout  about 
the  same  as  in  normal  patients. 

Pfeiffer  "  was  the  first  to  call  attention  to  the  fact  that  the 
excretion  of  uric  acid  is  higher  in  an  acute  attack  of  gout  than  in 
the  interval  between  attacks.  The  author,  unfortunately,  used 
the  inaccurate  Heinz  method  of  analysis,  but  his  discovery  has 
been  confirmed  by  Magnus-Levy/^  who  determined  the  uric  acid 
by  an  accurate  method.  Vogel  ^^  found  that  there  is  a  gradual 
increase  in  the  daily  excretion  of  uric  acid  for  several  days  after 

1  F.  Levison.  The  Uric  Acid  Diathesis,  Gout,  Sand,  and  Gravel.  Transl.  by  L.  Scott. 
London  (1894). 

2  E.  SchmoU.  Stoffwechselversuch  an  einem  Gichtkranken.  Zeitschr.  fur  klin.Med., 
29,  510  (1896). 

3  Camerer.  Beitrag  zur  Erforschung  der  StickstoShaltigen  Bestandtheile  des  mensch- 
lichen  Urins,  insbesondere  der  sogenannten  Alloxurkorper.  Zeitschr.  fiir  BioL,  35, 206 
(1897),  also 

Ibid.  Der  Gehalt  des  menschlichen  Urins  an  stiokstoffhaltigen  Korpern,  seine  Aciditat: 
die  Acidose  bei  der  Urinanalyse.     Tubingen  (1901). 

4L.  Badt.  Harnsaure  oder  Alloxurdiathese?  Zeitschr.  fiir  kUn.  Med.,  34,  359  (1898), 
also 

Ihid.  Ueber  Harnsaureausscheidung  im  Urin  wahrend  des  acuten  Gichtanfalles 
Zeitschr.  fiir  Min.  Med.,  67,  546  (1899). 

5  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  W  ochenschrift, 
21,  655  (1895). 

6  C.  Martin.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  bei  Nephritis 
Centralblatt  fiir  innere  Medizin,  20,  625  (1899). 

'G.  Zagari.  II  Bilancio  organico  di  un  Gottosa  durante  e  fuori  1' access o.  Napoli 
(1898). 

*W.  Bain.  The  Action  of  Various  Drugs  and  Diets  on  the  Excretion  of  Nitrogen  in 
Gout.     Brit.  Med.  Joum.  (1900),  I,  834. 

"M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologie 
der  Gicht.  II  Theil.  Ueber  Alloxurkorperausscheidung  unter  pathologischen  Verhalt- 
nissen.     Deutsche  Arch,  fiir  khn.  Medizin,  74,  348  (1902). 

loW.  J.  Grossman.  Zur  Kenntniss  des  Harnsaurestoffwechsels  und  des  Harnindicans 
bei  Gichtkranken.     Berl.  klin.  Wochenschrift,  40,  539  (1903). 

11 E.  Pfeiffer.  Die  Natur  und  Behandlung  der  Gicht.  Verhandl.  des  8t  Kongr. 
fiir  innere  Medizin  (1889),  p.  166,  also 

Ihid.     Die  Gicht  und  ihre  erfolgreich  Behandlung.     Wiesbaden  (1891),  2  Aufl.,  and 

Ihid.  Ueber  die  Ausscheidung  im  LTrin  wahrend  des  acuten  Gichtanfalles  mit  beson- 
derer  Beruchtsichtigung  der  Harnsaure.     Berl.  klin.  Wochenschrift,  33,  319  (1896). 

12 A.  Magnus-Levy.  Ueber  Gicht.  Zeitschr.  fiir  klin.  Med.,  36,  412  (1898),  and 
Beitrage  zum  Stoffwechsel  bei  Gicht.  Berl.  klin.  Wochenschrift,  33,  pp.  389  and  416 
(1896). 

13  L.  Vogel.     Ueber  Gicht.     Zeitschr.  fur   klin.  Med.,  24,  512  (1894),  also 

Ihid.  Ueber  den  Stoffwechsel  bei  Gichtkranken.  Enthalten  in  einem  Vortrag  v.  Noor- 
den's  Beitrage  zur  Ernahrungslehre  nach  Versuchen  von  Dr.  Kayser,  Krug,  Dapper, 
Vogel.  Sitzungsber.  der  physiol.  Gesellsch.,  Berl.,  17  Febr.,  1893;  Du  Bois  Archiv,  377 
(1893),  and  in  von  Noorden's  Beitrage  zur  Lehre  vom  Stoffwechsel.,  Berl.  (1894),  H.  2. 


Pathology  277 

the  onset  of  an  acute  attack.  Watson  ^  confirmed  both  Magnus- 
Levy  and  VogeL  His  ^  found  that  the  daily  excretion  of  uric 
acid  is  decreased  for  two  or  three  days  before  the  acute  attack. 
With  the  onset  of  the  attack,  excretion  of  uric  acid  begins  to 
increase.  The  increase  reaches  a  maximum  in  from  one  to  five 
days,  and  then  gradually  decreases  to  the  normal  value.  This 
work  of  His  has  been  confirmed  in  detail  by  Waldvogel  ^  and  by 
Futcher.* 

After  feeding  thymus  or  nuclein,  there  is  an  increased  excretion 
of  uric  acid  in  gout  as  in  health,  according  to  the  experiments  of 
Klemperer,^  ten  Cate,^  Bain,^  Watson,^  and  Schmoll."  Vogt  ^^ 
and  Reach  "  observed  an  increased  excretion  of  uric  acid  after 
nuclein  in  gout,  but  the  quantity  of  uric  acid  as  excreted  was  not 
so  great  as  after  the  same  quantity  of  nuclein  in  health. 

Soetbeer  ^^  carried  out  a  series  of  experiments  on  gouty  patients, 
and  compared  his  results  with  those  obtained  by  Pfeil  '^  on  healthy 
subjects.     He  collected  the  urine  for  analysis  at  intervals  of  three 

1  C.  Watson.  Observations  on  General  Metabolism  and  the  Blood  in  Gout.  Brit.  Med. 
Journ.,  1,  10  (1900).    " 

2W.  His.  Untersuchungen  an  Gichtkranken.  Wien.  med.  Blatter,  19,  291  (1896), 
also 

Ibid.  Untersuchungen  an  Gichtkranken.  Deutsche  med.  Wochenschrift,  22,  186 
Ver.   (1896),  also 

Ihid.  Die  Ausscheidung  von  Harnsaure  im  Urin  der  Gichtkranken  mit  besonderer 
Beriicksichtigung  der  Anfallzeiten  und  bestimmter  Behandlungsmethoden.  Deutsche 
Arch,  fur  klin.  Medizin,  65,  156  (1900). 

3  Waldvogel.  Der  Stoffwechsel  im  Gichtanfall.  Centralbl.  fiir  Stoffwechsel  und 
Verdauungskrankheiten,  3,  1  (1902). 

■*  F.  Futcher.  Some  Points  on  the  Metabolism  in  Gout;  with  Special  Reference  to 
Relationship  between  the  Uric  Acid  and  the  Phosphoric  Acid  EHmination  in  the  Intervals 
and  during  Acute  Attacks.     Practitioner,  London,  71,  181  (1903). 

^  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
schrift, 21,  665  (1895). 

^B.  ten  Gate.     Beitrage   zur  gichtischen  Diathese.     Inaug.   Dissert.,  Gottingen  (1899). 

''W.  Bain.  An  Experimental  Contribution  to  the  Study  of  Gout.  Brit.  Med.  Journ. 
(1899),    II,    1164. 

*  C.  Watson.  MetaboUsm  in  Gout  with  Observations  on  the  Action  of  Salicylate  of 
Soda  and  Nucleic  Acid.     Journ.  of  Path.,  7,  103  (1901). 

'  E.  Schmoll.  Stoffwechselversuch  an  einem  Gichtkranken.  Zeitschr.  fiir  klin.  Med., 
29,  510  (1896),  also 

Ihid.  Einige  Bemerkungen  zur  Therapie  der  Gicht.  Centralblatt  fiir  innere  Medizin, 
19,  1065  (1898). 

i^H.  Vogt.  Ein  Stoffwechselversuch  bei  acute  Gicht.  Deutsche  Arch,  fiir  klin.  Medizin, 
71,  24  (1901). 

^1  F.  Reach.  Ein  Beitrag  zur  Kenntniss  des  Stoffwechsels  bei  der  Gicht.  Munchen 
med.  Wochenschrift  (1902),  1215. 

'^F.  Soetbeer.  Ueber  die  Einfluss  der  Nahrungsaufnahme  auf  die  Ausscheidung  der 
Harnsaure  bei  Arthritis  urica.     Zeitschr.  fiir  physiol.  Chem.,  40,  25  (1903). 

12  P.  Pfeil.  Ueber  den  Einfluss  der  Nahrungsaufnahme  auf  die  Ausscheidung  der  Harn- 
saure.    Zeitschr.  fiir  physiol.  Chem.,  40,  1  (1903). 


278      The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

hours.  The  results  showed  that  the  excretion  of  uric  acid  after 
food  containing  nucleins  and  purin  bodies  is  not  at  all  so  high  as 
in  health,  and  that  the  increased  excretion  does  not  appear  so 
soon.  In  some  cases  there  was  absolutely  no  increased  excretion 
of  uric  acid  after  a  change  from  a  purin  free  diet  to  one  containing 
purin  bodies.  The  excretion  of  uric  acid  was  found  to  be  much 
lower  in  two  gouty  patients  than  in  two  healthy  patients  on  the 
same  diet.^ 

It  will  be  well  to  speak  here  of  Neusser's  discovery .^  This 
author  observed  granules  around  the  nuclei  of  the  leucocytes  in 
gouty  blood  which  stain  black  with  Ehrlich's  triacid  mixture. 
This  was  interpreted  to  mean  an  overproduction  of  nuclein 
material.  Futcher,^  however,  observed  these  granules  in  the 
leucocytes  in  other  diseases,  and  did  not  always  find  them  in  gout. 
Ehrlich  '*  thinks  that  the  results  of  Neusser  are  due  to  the  use 
of  impure  reagents. 

METABOLISM  OF  PURIN  BASES 
Kolisch  ^  found  the  uric  acid  excretion  low  and  the  excretion 
of  purin  bases  high  in  gout,  and  attempted  to  base  a  theory  of 
gout  on  his  observations.  Croftan  "^  likewise  found  the  ratio 
of  the  purin  bases  to  uric  acid  high  in  gouty  urine.  Both  of 
these  experimenters  used  the  inaccurate  Kriiger-Wulf  method 
in  their  experiments,  a  fact  which  makes  their  work  valueless. 
We  have  already  seen  that  the  uric  acid  excretion  is  not 
low    in    gout.      Further,    neither    Ziilzer,^    Malfatti,^    Laquer,^ 

IF.  Soetbeer.  Ein  Stoffwechselversuch  bei  Gicht.  Zeitschr.  fur  physiol.  Chem. . 
40,  55  (1903). 

2  E.  Neusser.  Ueber  einen  besonderen  Blutbefund  bei  uratischer  Diathese.  Wien.  klin. 
Wochenschrift,  7,  727  (1894). 

3  T.  Futcher.  Ueber  den  Zusaminenhang  zwischen  der  sogennanten  perinuclear  baso- 
philie  und  der  Ausschiedung  der  Alloxurkorper  im  Ham.  Centralblatt  fiir  klin.  Medizin, 
17,  985  (1896). 

■*  Ehrlich  und  Lazarus.     Die  Anamie.    Nothnagel's  Handbuch,  Bd.  8,  Wien  (1898). 

■'  R.  Kolisch.  Ueber  Wesen  und  Behandlung  der  Gicht.  Wien.  klin.  Wochenschrift, 
8,  787  (1895),  also, 

R.  Kolisch  und  Dostal.  Das  Verhalten  der  Alloxurkorper  im  pathologischen  Harn. 
Wien.  klin.  Wochenschrift,  8,  413,  and  435  (1895),  also 

R.  Kolisch.     Ueber  Wesen  und  Behandlung  der  uratischen  Diathese.     Stuttgart  (1895). 

f'  A.  Croftan.  An  Investigation  into  the  Causes  of  So-Called  Uric  Acid  Lesions  and  a 
Rational  Therapeutics  of  the  Uratic  Diathesis.     N.  Y.  Med.  Journ.,  72,  221  (1900). 

'  G.  Zulzer.  Ueber  die  Alloxurkorperausscheidung  im  Harn  bei  Nephritis.  Berl.  klin. 
Wochenschrift,  33,  72  (1896). 

*  H.  Malfatti.  Ueber  die  Alloxurkorper  und  ihr  Verhaltniss  zur  Gicht.  Wien.  klin. 
Wochenschrift,  9,  723  (1896). 

'  B.  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  im  Harne  von 
Gesunden  und  Kranken.     Verhandl.  des  14t  Kongr.  fiir  innere  Medizin,  333  (1896). 


Pathology  279 

Schmoll/  Albu,-  Camerer/  Strauss,^  Badt;'  Martin,"  Bain  ^  nor 
Kaufmann  and  Mohr  **  could  find  that  the  excretion  of  purin 
bases  is  increased,  or  that  the  ratio  of  the  quantity  of  purin 
bases  to  uric  acid  is  increased  in  gout. 

METABOLISM  OF  NITROGEN  AND  FAT 

Vogel  ^  was  the  first  to  observe  that  there  is  a  disturbance  in 
the  metabolism  of  nitrogen  in  gout.  In  one  case  he  found  a 
retention  of  13.10  grams  nitrogen  during  five  days  of  an  acute 
attack.  In  another  case  there  was  a  retention  of  from  one  to 
seven  grams  a  day  for  fourteen  days.  In  a  third  case  there  was 
an  average  retention  of  from  four  to  seven  grams  per  day  for  ten 
days.  Laquer,^**  Vogt,^^  and  Schmoll  ^  confirmed  Vogel's  obser- 
vations. Schmoll  ^  found  a  retention  of  34  grams  nitrogen  in  ten 
days. 

'  E.  Schmoll.  Stoffwechselversuch  an  einem  Gichtkranken.  Zeitschr.  fiir  klin.  Med., 
29,  510  (1896),  also 

Ibid.  Einige  Bemerkungen  zur  Theorie  der  Gicht.  Centralblatt  fiir  innere  Medizin, 
19,   1065  (1898). 

-  Albu,  in  Discussion  of  Laquer's  article.  Ueber  die  Ausscheidungsverhiiltnisse  der 
Alloxurkorper  im  Harne  von  Gesunden  und  Kranken.  Verhandl.  des  14t  Kongr.  fiir  innere 
Medizin,  423   (1896). 

3  Camerer.  Beitrag  zur  Erforschung  der  stickstoffhaltigen  Bestandtheile  des  mensch- 
lichen  Urins,  insbesondere  der  sogenannten  Alloxurkorper.  Zeitschr.  fiir  Biol.,  35,  206 
(1896). 

•*  J.  Strauss.  Ueber  die  Einwirkung  des  kohlensauren  Kalkes  auf  den  menschlichen 
Stoffwechsel,  ein  Beitrag  zur  Therapie  der  harnsauren  Nierenconcretionen  nebst  Bemerk 
ungen  iiber  Alloxurkorperausscheidung.     Zeitschr.  fiir  klin.  Med.,  31,  493  (1897). 

''  L.  Badt.  Harnsaure  oder  AUoxurdiathese?  Zeitschr.  fiir  klin.  Med.,  34,  359 
(1898). 

"  C.  Martin.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  bei  Nephritis. 
Centralblatt  fur  innere  Medizin,  20,  625  (1899). 

''  W.  Bain.  An  Experimental  Contribution  to  the  Studj'  of  Gout.  Brit.  Med.  Journ. 
(1899),  II,  1164,  also 

The  Action  of  Various  Drugs  and  Diets  on  the  Excretion  of  Nitrogen  in  Gout.  Brit. 
Med.  Journ.  (1900),  1,  834. 

*  M.  Kaufmann  und  li.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologie  der 
Gicht.  II  Theil.  Ueber  Allo.xurkorperausscheidung  unter  pathologischen  Verhalt- 
nissen.     Deutsche  Arch,  fiir  klin.  Medizin,  74,  384  (1902). 

"  L.  Vogel.  Ueber  den  Stoffwechsel  bei  Gichtkranken.  Enthalten  in  einem  Vortrag 
V.  Noorden's  Beitrage  zur  Ernahrungslehre  nach  Versuchen  von  Dr.  Kayser,  Krug,  Dapper, 
und  Vogel.  Sitzungsber.  des  physiol.  Gesellsch.,  Berlin,  17  Febr.,  1893;  Du  Bois  Archiv, 
377  (1893),  also 

In  von  Noorden's  Beitrage  zur  Lehre  vom  Stoffwechsel.     Berlin  (1894),  Heft.  2,  also 

"L.  Vogel.     Ueber  Gicht.     Zeitschr.  fiir  klin.  Med.,  24,  512  (1894). 

1°  B.  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  im  Harn  von 
Gesunden  und  Kranken.     Verhandl.  des  14t  Kongr.  fiir  innere  Medizin,  333  (1896). 

'^  H.  Vogt.  Ein  Stoffwechselversuch  bei  acute  Gicht.  Deutsche  Arch,  fiir  klin.  Med.. 
71,  21    (1901). 


280      The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

According  to  the  experiments  of  Magnus-Levy/  the  metab- 
olism of  nitrogen  in  gont  resembles  somewhat  the  metabolism  of 
nitrogen  in  certain  kidney  diseases.  There  are  alternate  periods 
of  nitrogen  retention  and  nitrogen  loss.  Magnus-Levy  found  that 
the  period  of  nitrogen  loss  was  usually  during  the  attack,  and 
the  period  of  nitrogen  retention  after  the  attack.  Futcher,^  too, 
found  the  excretion  of  nitrogen  high  during  an  acute  attack  of 
gout.  Camerer  ^  and  Zagari  *  found  alternate  periods  of  nitrogen 
loss  and  nitrogen  retention.  According  to  Zagari,*  the  period  of 
nitrogen  loss  is  usually  coincident  with  that  of  the  acute  attack, 
but  not  always.  In  one  case  of  Laquer's,'^  the  nitrogen  excretion 
on  two  successive  days  was  5.2  grams  and  22.9  grams  re- 
spectively. 

Both  Vogel  and  Magnus-Levy  showed  that  the  body  weight 
did  not  increase  with  nitrogen  retention  and  decrease  with  the  loss 
of  nitrogen  in  these  cases.  Further,  the  quantity  of  food  given, 
reckoned  in  calories,  was  in  most  cases  about  the  proper  quan- 
tity. In  some  cases  the  quantity  given  was  increased  or  dimin- 
ished, but  this  did  not  seem  to  affect  the  peculiar  results.  We 
cannot  state  in  what  form  the  nitrogen  is  retained  in  gout.  Ac- 
cording to  Loewi,  it  is  retained  as  uric  acid.  But  Loewi  ^  based 
this  view  on  the  erroneous  assumption  that  the  quantity  of 
endogenous  uric  acid  excreted  per  day  is  the  same  for  all  persons. 

Watson  ^  found  in  one  case  an  increase  in  urea  during  an  attack. 
Pfeiffer  ^  found  the  urea  high  during  an  attack  and  low  after  an 
attack. 

1  A.  Magnus-Levy.  Beitrage  zum  Stoffwechsel  bei  Gicht.  Berl.  klin.  Wochenschrift, 
33,  pp.  389  and  416  (1896),  also 

Ihid.     Ueber  Gicht.     Zeitschr.  fiir  klin.  Med.,  36,  353  (1898). 

2  T.  Futcher.  Some  Points  on  the  Metabolism  in  Gout,  with  Special  Reference  to 
the  Relationship  between  the  Uric  Acid  and  the  Phosphoric  Acid  Elimination  in  the  In- 
tervals and  during  Acute  Attacks.     Practitioner,  Lond.,  71,  181  (1903). 

3  Camerer.  Beitrag  zur  Erforschung  der  stickstoffhaltigen  Bestandtheile  des  mensch- 
lichen  Urins,  insbesondere  des  sogenannten  AUoxurkorper.  Zeitschr.  fiir  Biol.,  35,  206 
(1897). 

^  G.  Zagari.  II  balancio  organico  di  un  gottosa  durante  e  fuori  I'accesso.  Napoli 
(1898). 

5  B.  Laquer.  Ueber  die  Ausscheidungsverhaltnisse  der  AUoxurkorper  im  Harn  von 
Gesunden  und  Kranken.     Verhandl.  des  14t  Kongr.  fiir  innere  Med.,  333  (1896). 

*  O.  Loewi.  Beitrag  zur  Kenntniss  des  Nucleinstoffwechsels.  I  Mittheilung.  Arch, 
ftir  exp.  Path.  u.  Pharm.,  44,  1  (1901). 

^  Watson.  Observations  on  General  Metabolism  and  the  Blood  in  Gout.  Brit.  Med. 
Journ.   (1901),  I,  10. 

*  E.  Pfeiffer.  Ueber  die  Ausscheidungen  im  Urin  wahrend  des  acuten  Gichtanfalles 
mit  besonderer  Berilcksichtigung  der  Harnsaure.  Berl.  klin.  Wochenschrift,  33,  319 
(1896). 


Pathology  281 

Another  peculiarity  of  the  metabolism  of  gout  is  the  great  loss 
of  nitrogen  in  the  feces.  In  several  cases  observed  by  Vogel/ 
the  quantity  of  nitrogen  in  the  feces  was  from  ten  to  fifteen  per 
cent,  as  much  as  that  in  the  food.  This  same  great  loss  was 
observed  in  the  experiments  of  Magnus-Levy,^  Schmoll,^  and 
Vogt/  except  that  in  one  of  Magnus-Levy's  cases  the  loss  was 
only  from  five  to  eight  per  cent. 

Kaufmann  and  Mohr  '"  found  the  absorption  bad  in  one  case  of 
gout.  In  three  cases  it  was  good;  only  five  to  eight  per  cent,  of 
the  amount  of  nitrogen  in  the  food  was  found  in  the  feces.  Fur- 
ther, Kaufmann  and  Mohr  found  the  P2O5  in  the  feces  increased 
more  in  gout  after  thymus  than  in  health,  and  assumed  that  this 
indicates  poor  absorption  of  nucleoproteid.  This  conclusion  is 
not  warranted.  The  amount  of  P2O5  in  the  feces  does  not  depend 
wholly  on  the  amount  unabsorbed  from  the  food,  but  on  other 
factors;  the  amount  of  calcium  in  the  food,  for  example,  being 
one  of  them. 

The  increase  in  nitrogen  in  the  feces  is  not  necessarily  due  to 
unabsorbed  food.  It  may  be  due  to  increased  secretion  or  ex- 
cretion in  the  digestive  tract.  The  fact  observed  by  Vogel  ^ 
that  all  but  about  five  to  seven  per  cent,  of  the  fat  is  absorbed 
indicates  that  we  probably  do  not  have  a  condition  of  poor  ab- 
sorption. Magnus-Levy  "  found  that  nine  to  ten  per  cent,  of  the 
fat  of  the  food  is  left  unabsorbed.  This  is  not  exceedingly  high. 
Adler ''  has  suggested  that  the  high  nitrogen  content  of  the  feces 
is  due  to  intestinal  fermentation.  There  are  evidences  of  intes- 
tinal fermentation  in  gout,  as  we  shall  see. 

1  L.  Vogel.  Ueber  den  Stoffwechsel  bei  Gichtkranken.  Enthalten  in  einem  Vortrag 
von  Noorden's  Beitrage  zur  Ernahrungslehre  nach  Versuchen  von  Dr.  Kayser,  Kiug, 
Dapper,  Vogel.  Sitzungsber.  der  physiol.  Gesellsch.,  Berlin,  17  Febr.,  1893 ;  Du  Bois  Archiv, 
377  (1893),  and  in  von  Noorden's  Beitrage  zur  Lehre  vom  Stoffwechsel,  Berlin  (1894), 
Heft.  2,  also 

Ihid.     Ueber  Gicht.    Zeitschr.  fur  klin.  Med.,  24,  512  (1894). 

2  A.  Magnus-Levy.  Beitrage  zum  Stoffwechsel  bei  Gicht.  Berl.  klin.  W^ochenschrift, 
33,  pp.  389  and  416  (1896),  also 

Ibid.     Ueber  Gicht.     Zeitschr.  fur  klin.  Med.,  36,  353  (1898). 

3  E.  Schmoll.  Stoffwechselversuch  an  einem  Gichtkranken.  Zeitschr.  fiir  klin.  Med-,  29, 
510  (1896). 

■*  H.  Vogt.  Ein  Stoffwechselversuch  bei  acute  Gicht.  Deutsche  Arch,  fiir  klin.  Med.,  71, 
21   (1901). 

5  M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologic  der 
Gicht.     Deutsche  Arch,  fiir  klin.  Med.,  76,  586  (1902). 

*A.  Magnus-Levy.  Beitrage  zum  Stoffwechsel  bei  Gicht.  Berl.  klin.  Wochenschrift, 
33,  pp.  389  and  416  (1896). 

^  A.  Adler.  Zum  Verstandniss  einiger  gichtischer  Erscheinungen.  Deutsche  med. 
Wochenschrift,  27,  86  (1901). 


282      The  Chemistry,  Physiology ,  and  I^athology  of  Uric  Acid 

METABOLISM  OF  PHOSPHORUS,  POTASSIUM,  INDICAN,  ETC. 

The  early  writers  disagreed  ccmcerning  the  metabolism  of 
phosphoric  acid  in  gout.  According  to  Bocker,^Parkes,^  Stokvis,^ 
and  Jones,*  the  P2O5  in  the  urine  is  low.  Berthollet  ^  and  Scuda- 
more  ^  found  it  high.  Lecorche  *  stated  that  it  varies  with  the 
uric  acid  excretion. 

According  to  Schmoll,''  the  excretion  of  P2O5  in  gout  is  normal. 
Watson  ^  found  a  marked  diminution  in  the  excretion  of  P2O5 
during  the  first  few  days  of  an  acute  attack,  followed  by  an 
equally  marked  increased  excretion.  WaldvogeP  observed  the 
same  result. 

Vogt's  ®  experiments  seem  to  indicate  that  when  nucleins  are 
fed  to  a  gouty  person,  some  of  the  uric  acid  formed  from  the  purin 
is  retained,  whereas  the  P2O5  is  immediately  excreted.  Ten 
Cate^°  and  Kaufmann  and  Mohr"  find  that  the  opposite  is  true. 
When  nucleins  are  fed,  the  P2O5  is  retained  and  the  uric  acid 
excreted.  Futcher  ^^  found  the  P2O5  excretion  low  in  gout,  but 
parallel  with  that  of  uric  acid.  The  P2O5  in  the  urine  is  not  a 
measure  of  the  total  P2O5  excretion.  A  variable  amount,  de- 
pendent somewhat  on  the  quantity  of  calcium  excreted,  is  found 
in  the  feces,  so  that  we  should  expect  somewhat  discordant 
results. 

1  Bocker.  Zur  Pathologic  der  Gicht.  Rhein  Monatsh.,  Feb.  (1850),  and  Canstatts, 
Jahresb.   (1850),   158. 

2  E.  Parkes.  The  Composition  of  the  Urine  in  Health  and  Disease  and  under  the  Action 
of  Remedies.     London  (1860). 

3  B.  Stokvis.  Zur  Kenntniss  der  Phosphorausscheidung  bei  Arthritis.  Centralblatt 
fur  med.  Wissensch.,  13,  801  (1875). 

*  D.  Duckworth.     A  Treatise  on  Gout.     London  (1890). 

5  C.  Bouchard.     Maladies  par  ralentissement  de  la  Nutrition.    Paris  (1882). 

8  E.  SchmoU.  Stoffwechselversuch  an  einem  Gichtkranken.  Zeitschr.  fiir  klin.  Med., 
29,  510  (1896). 

^G.  Watson.  Observations  on  General  Metabolism  and  the  Blood  in  Gout.  Brit. 
Med.  Journ.,  1,  10  (1900),  also 

Ibid.  Metabolism  in  Gout,  with  Observations  on  the  Action  of  Salicylate  of  Soda 
and  Nucleic  Acid.     Journ.  of  Path.,  7,  103  (1901). 

8  Waldvogel.  Der  Stoffwechsel  in  Gichtanfall.  Centralbl.  fiir  Stoffwechsel  und 
Verdauungskrankheiten,  3,    1   (1902). 

^  H.  Vogt.  Ein  Stoffwechselversuch  bei  acute  Gicht.  Deutsche  Arch,  fiir  klin.  Med., 
71.  21  (1901). 

i^B.  ten  Gate.    Beitrage  zur  gichtischen  Diathese.     Inaug.  Dissert.,  Gottingen  (1899). 

11 M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  AUoxurkorperfrage  und  zur  Pathologie 
der  Gicht.  Ill  Theil.  Stoffwechselbeobachtungen  bei  5  Gichtkranken.  Deutsche  Arch, 
fur  klin.  Med.,  74,  586  (1902). 

i-T.  Futcher.  Some  Points  on  the  Metabolism  in  Gout,  with  Special  Reference  to 
the  Relationship  between  the  Uric  Acid  and  the  Phosphoric  Acid  Elimination  in  the 
Intervals  and  during  Acute  Attacks.     Practitioner,  71,  181  (1903). 


Pathology  283 

Soetbeer  ^  found  the  excretion  of  potassium  in  two  cases  of  gout 
low,  compared  with  that  in  two  healthy  persons  living  on  the 
same  diet. 

Magnus-Levy  ^  found  the  indican  in  the  urine  enormously 
increased  in  gout,  an  indication  of  intestinal  fermentation. 
Grossman  ^  found  the  indican  rather  low  in  gout  on  a  milk  diet. 
The  significance  of  this  is  probably  important  from  a  chemical 
standpoint,  for  some  observers  have  found  good  clinical  results 
from  milk  diet  in  gout. 

Hall  *  found  the  excretion  of  aromatic  sulphates  high  in  gout. 
This  is  considered  an  indication  of  intestinal  putrefaction. 

According  to  Ebstein'*^  and  others, glycosuria  occurs  often  in  gout. 

We  will  conclude  this  sketch  of  the  metabolism  in  gout  with  a 
brief  sumanary  of  the  important  points. 

Concerning  the  metabolism  of  uric  acid,  we  may  say  that  the  ex- 
cretion of  uric  acid  gradually  increases  for  a  few  days  after  the  onset 
of  an  acute  attack  of  gout  and  then  gradually  decreases  to  normal. 

Different  authors  disagree  concerning  the  effect  of  nucleins  on 
the  excretion  of  uric  acid  in  gout.  Some  have  found  the  excretion 
of  uric  acid  increased  after  purin  food.  Others  have  confirmed 
this,  but  stated  that  the  increase  was  not  so  marked  as  in  health. 
Soetbeer,  who  appears  to  have  done  careful  work,  found  absolutely 
no  increase  in  the  excretion  of  uric  acid  after  purin  food  in  gout  in 
some  cases.  In  view  of  the  fact  that  digestive  disturbances  are  very 
marked  in  gout,  the  differences  may  possibly  be  due  to  differences 
in  absorption,  or  the  purin  may  be  destroyed  before  absorption. 

The  relation  between  the  purin  bases  and  uric  acid  in  the  urine ' 
in  gout  is  normal. 

The  metabolism  of  nitrogen  is  abnormal.  There  are  alternate 
periods  of  nitrogen,  retention  and  nitrogen  loss,  as  in  nephritis, 
without  corresponding  changes  in  the  body  weight.  According  to 
Magnus-Levy ,  the  periods  of  nitrogen  loss  are  coincident  with  those 

^  F.  Soetbeer.  Ein  Stoffwechselversuch  bei  Gicht.  Zeitsohr.  fiir  physiol.  Chem., 
40,   55   (1903). 

2  A.  Magnus-Levy.     Ueber  Gicht.     Zeitschr.  fur  klin.  Med.,  36,  353  (1898). 

3  J.  Grossman.  Zur  Kenntniss  des  Harnsaurestoffwechsels  und  des  Harnindicans  bei 
Gichtkranken.     Berl.  kJin.  Wochenschrift,  40,  539  (1903). 

*  I.  Hall.  Metabolism  in  Gout  and  the  Need  for  Combined  Investigation.  Practitioner, 
71,  61  (1903). 

5  W.  Ebstein.  Angina  Pectoris  neben  Arthritis  uratica  und  Diabetes  mellitus.  Berl. 
klin.  Wochenschrift,  32,  493,  522  and  545  (1895). 


284      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

of  acute  attacks,  and  the  nitrogen  retention  occurs  during  convales- 
cence. Other  experimenters  observed  nitrogen  retention  during 
acute  attacks  of  gout.  The  feces  are  usually  very  high  in  nitro- 
gen, though  according  to  Kaufmann  and  Mohr,  this  is  not  always 
the  case.  The  absorption  of  fat  is  good,  and  probably,  therefore, 
according  to  Vogel,  the  absorption  of  proteid  is  good,  so  that  the 
large  amount  of  nitrogen  in  the  feces  is  due  to  excretion  of  nitro- 
gen into  the  intestines,  or  comes  from  the  walls  of  the  intestines. 

The  results  obtained  by  different  authors  in  the  study  of  the 
metabolism  of  phosphorus  are  contradictory.  While  some  find  a 
retention  of  P2O5  after  nuclein  feeding,  others  find  the  P2O5 
excreted  just  as  in  normal  persons. 

It  is  plain  that  there  is  much  to  be  learned  concerning  the 
metabolism  in  gout.  We  hope  to  study  the  nitrogen  absorption 
and  the  metabolism  of  uric  acid  and  phosphorus  on  both  nuclein 
food  and  nuclein-free  food. 

Cause  of  the  Increased  Uric  Acid  in  the  Blood  in  Gout 

In  view  of  the  chemical  composition  of  gouty  concretions, 
the  fact  that  uri<}  acid  is  found  in  the  blood  in  gout  but  not  in 
health  seems  important.  We  shall,  therefore,  examine  the  differ- 
ent theories  which  have  been  offered  to  explain  its  presence.  It 
has  been  suggested  that  this  uric  acid  may  be  due  to  an  increased 
formation  of  uric  acid,  and  that  the  kidneys  cannot  excrete  it 
fast  enough  to  free  the  blood  of  it.  It  has  also  been  suggested 
that  the  uric  acid  is  retained  either  because  the  kidneys  are 
diseased,  or  because  the  uric  acid  is  not  combined  in  such  a  way 
that  it  can  be  excreted.  Further,  various  causes  might  contribute 
to  bring  about  a  decrease  in  the  amount  of  uric  acid  oxidized  to 
urea.  This  might  cause  the  presence  of  uric  acid  in  the  blood. 
There  is  another  possibility.  In  health,  uric  acid  may  be  in  the 
blood,  but  combined  as  an  organic  compound  in  such  a  way  as 
not  to  be  detected  by  our  usual  chemical  tests  for  uric  acid.  In 
gout  the  uric  acid  may  not  all  be  combined  in  this  way;  there- 
fore we  find  it  in  the  blood. 

INCREASED   FORMATION    OF  URIC   ACID 
According  to  Latham,^  the  primary  fault  in  gout  is  one  of  im- 
perfect metabolism  of  glycocine,  whereby  this  is  not  changed  to 

1  p.  Latham.  Some  Points  in  the  Pathology  of  Rheumatism,  Gout,  and  Diabetes. 
(Croonian  Lectures.)     Lancet  (1886),  I,  626,  672,  723,  771,  and  817. 


Pathology  285 

urea,  but  passes  into  the  kidney  and  there  combines  with  urea  to 
form  uric  acid.  It  is  then  reabsorbed  and  passes  into  the  cir- 
culation. Wiener^  likewise  believes  that  an  increase  in  the 
amount  of  uric  acid  formed  by  synthesis  may  account  in  part  for 
the  presence  of  uric  acid  in  the  blood  in  gout. 

We  have  already  seen  that  there  is  no  evidence  to  show  that 
uric  acid  is  formed  by  synthesis  from  urea  and  glycogen  in  the 
body,  but,  on  the  other  hand,  good  evidence  to  show  that  uric 
acid  is  not  found  in  this  manner. 

Ord  ^  believed  that  there  is  increased  formation  of  uric  acid  in 
all  parts  of  the  body  in  gout.  According  to  Levison  ^  there  may 
be  increased  leucolysis,  and  according  to  Pfeiffer,  a  rapid  ka- 
tabolism  of  the  cells  generally  in  gout.  Klemperer  ^  and  Luthje  •'^ 
likewise  think  that  there  is  an  increased  formation  of  uric  acid  in 
gout.  Ebstein  ^  beheves  that  in  gout  there  is  an  increased 
formation  of  uric  acid  from  nucleins  in  perverse  places,  such 
as  the  muscles,  cartilage,  bone  marrow,  etc.  He  defines  the 
uric  acid  diathesis  as  a  pathological  disposition  of  man,  in  con- 
sequence of  which,  without  known  functional  or  organic  primary 
disturbance,  more  uric  acid  is  formed  than  normally.  None  of 
these  authors  offer  experimental  evidence  in  support  of  their 
views. 

We  should  scarcely  expect  the  presence  of  uric  acid  in  the  blood 
to  be  due  to  increased  formation  alone.  It  would  be  necessary 
to  assunie  also  that  there  is  a  decreased  power  of  the  kidneys  to 
excrete  uric  acid,  for  healthy  kidneys  can  excrete  far  more  uric 
acid  per  day  than  has  ever  been  observed  in  cases  of  gout.  In 
leukemia,  three  to  four  grams  uric  acid  per  dp,y  are  sometimes 
found  in  the  urine. 

'  Hugo  Wiener.  Die  Harnsaure  in  ihrer  Bedeutung  fiir  die  Pathologie.  Ergebnisse 
der  Physiologie  von  Ascher  und  Spiro,  II  Jahrgang,  I  Abtheilung,  411  (1903). 

2  Ord.     Relation  of  Uric  Acid  to  Gout.     Med.  Times  and  Gazette,  1,  233  (1874). 

3  F.  Levison.  Die  Harnsaure  als  Krankheitsursache.  Arch.  f.  Verdauungskrankheiten, 
3,  478  (1898). 

*  G .  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Deutsche  med.  Wochen- 
schrift,  21,  6.55  (1895). 

5  H.  Luthje.  Ueber  Bleigicht  und  den  Einfluss  der  Bleiintoxikationen  auf  die  Harn- 
saureausscheidung.     Zeitschr.  fiir  klin.  Med.,  29,  266  (1896). 

^W.  Ebstein.  Beitrage  zur  Lehre  von  der  harnsauren  Diathese.  Wiesbaden  (1891); 
also 

Ibid.  Ueber  die  Stellung  der  Fettleibigkeit  die  Gicht  und  der  Zuckerkrankheit 
im  nosologischen  System.  Verhandl.  der  70  Naturforscherversammlung  in  Diisseldorf. 
Abtheilung  fiir  innere  Med.     Deutsche  med.  Wochenschrift,  24,  693  (1898). 


286      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 


RETENTION   OF   URIC  ACID 

The  theory  that  the  kidneys  are  so  affected  in  gout  that  they 
fail  to  excrete  the  uric  acid  as  fast  as  it  is  brought  to  them,  and 
thus  cause  retention  of  uric  acid  in  the  blood,  has  been  a  favorite 
one,  and  has  much  to  support  it.  Garrod  ^  first  suggested  this 
theory.  According  to  this  author,  the  kidneys  are  always  affected 
in  the  early  stages  of  gout,  and  often  before  any  symptoms  of  the 
disease  appear.  He  found  uric  acid  in  the  blood  not  only  in  gout, 
but  in  cases  of  albuminuria  and  lead  poisoning.  Further,  the 
decreased  excretion  of  uric  acid  observed  by  Garrod  in  gout  was 
an  argument  in  favor  of  his  theory. 

For  a  long  time  it  was  difficult  to  oppose  this  theory.  All  the 
early  experimenters,  using  the  Heinz  method  of  determination, 
found  the  excretion  of  uric  acid  low  in  gout,  and  Becquerel,^ 
Gorup-Besanez,^  Frerichs,*  Dickinson,^  Bartels,®  Fleischer,^  and 
Wagner/  who  likewise  used  the  Heinz  method,  found  the  excre- 
tion of  uric  acid  low  in  nephritis. 

Uric  acid,  as  we  have  seen,  has  been  found  in  the  blood  in 
kidney  diseases  and  in  cases  of  lead  poisoning,  and  lead  poison- 
ing predisposes  to  both  nephritis  and  gout.  From  Garrod's  time 
up  to  the  present,  most  of  those  who  have  devoted  attention  to 
the  subject  have  found  indications  of  lead  poisoning  in  a  large 
percentage  of  the  cases  of  gout.  According  to  Luthje,^  who 
studied  the  subject  historically  as  well  as  experim.entally,  lead 
poisoning  alone  may  cause  gout. 

The  frequent  occurrence  of  cases  of  both  kidney  disease,  espe- 
cially contracted  kidney  or  granular  atrophy,  and  gout  in  a  single 
individual  has  led  some  authors  to  believe  that  there  is  a  causal 

1  A.  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheiimatism,  and  Bright's  Disease.      Medico-Chirurg.  Trans.,  31,  83  (1848),  also 

Ihid.     The  Nature  and  Treatment  of  Gout  and  Rheumatic  Gout.     London  (1859). 

^  Becquerel.  Semeiotique  des  urines  ou  traits  des  alterations  de  I'urine  dans  les  maladie.? 
suivi  d'un  traits  de  la  maladie  de  Bright.     Paris  (1841),  509. 

3  Gorup-Besanez.     Arch.  f.  physik.  Heilk.,  8,  712  (1849). 

■*  Frerichs.  Die  Bright 'sche  Nierenkrankheit  undderenBehandlung.  Braunschweig  (1851). 

s  Dickinson.     Diseases  of  the  Eadneys  and  Urinary  Derangements.     London  (1875). 

^  Bartels.  Nierenkrankheiten.  Ziemssen's  Handbuch  der  spec.  Path,  und  Therap., 
9,  1  (1877),  2d  ed.,  p.  407. 

'  R.  Fleischer.  Klinisehe  und  pathologisch-chemische  Beitrage  zur  Lehre  von  der 
Nierenkrankheiten.     Deutsche  Arch,  fiir  klin.  Medizin,  29,  129  (1881). 

*  E.  Wagner.  Der  Morbus  Brightii.  Ziemssen's  Handbuch  der  spec.  Path,  und  Therap., 
9,   1    (1882). 

'  C.  Luthje.  L^eber  Bleigioht  und  den  Einfluss  der  Bleiintoxikation  auf  die  Harn- 
saureausscheidung.     Zeitschr.  fur  klin.  Med.,  29,  266  (1896). 


Pathology  287 

relation  between  the  two.  According  to  Levison/  no  case  has 
ever  been  reported  in  the  literature  of  a  gouty  person  carefully 
examined  at  autopsy  in  which  the  kidneys  were  normal.  Luff,^ 
Moore,^  and  many  other  observers  find  that  a  large  proportion 
of  those  who  have  had  gout  show  evidences  of  kidney  disease  at 
autopsy.  Further,  many  observers  have  noted  that  urate  con- 
cretions are  frequently  found  at  the  autopsy  of  those  who  have 
suffered  from  certain  forms  of  kidney  disease.  According  to 
Kam/  at  the  time  of  the  onset  of  an  attack  of  acute  nephritis,  the 
uric  acid  excretion  is  low.  It  gradually  increases  and  then  on 
convalescence  decreases  to  slightly  below  normal.  This  is  very 
similar  to  the  behavior  of  the  uric  acid  in  an  acute  attack  of  gout, 
and,  if  it  is  confirmed,  will  be  another  point  in  favor  of  the  reten- 
tion theory.  These  facts,  together  with  the  fact  that  uric  acid 
is  found  in  the  blood  in  nephritis,  lend  strong  support  to  the 
theory  that  the  presence  of  uric  acid  in  the  blood  in  gout  is  due 
to  kidney  disease,  whereby  there  is  failure  on  the  part  of  the 
kidneys  to  excrete  uric  acid. 

All  observers  do  not  admit  that  there  is  a  close  clinical  con- 
nection between  gout  and  kidney  disease.  According  to  Cantani  ^ 
and  Ebstein  there  is  usually  no  kidney  disease  in  the  early  stages 
of  gout.  Vogt  ^  maintains  that  there  can  be  gout  without  kidney 
disease,  for,  in  a  case  of  gout  w^here  thymus  was  fed,  the  P2O5  from 
the  thymus  w^as  excreted,  and  Fleischer^  has  shown  that  the  P2O5 
excretion  is  always  low  in  nephritis.  Futcher^  thinks  that  the 
fact  that  the  excretion  of  uric  acid  .is  highest  during  an  acute 
attack  argues  against  the  view  that  the  presence  of  uric  acid  in  the 

1  F.  Le\dson.  Zur  Lehre  von  den  Pathogenese  der  Gicht.  Zeitschr.  fiir  klin.  Med.,  26, 
293    (1894). 

2  A.  Luff.  The  Chemistry  and  Pathology  of  Gout.  (Goulstonian  Lecttires.)  Lancet 
(1897),  T,  857,  942,  and  1069,  also 

Ihid.     Gout,  Its  Pathology  and  Treatment.     New  York  (1899). 

3  N.  Moore.  Some  Observations  on  the  Morbid  Anatomy  of  Gout.  St.  Bartholomew's 
Hospital  Reports,  23,  289  (1887). 

*  B.  Kam.  Bijdrage  to  de  kenis  der  urinezuur-uitscheidung.  Dissert.,  Leiden  (1898), 
Maly's  .Jahresb.  uber  die  Fortschritte  der  Thierchemie,  28,  573  (1898). 

5  A.  Cantani.  Oxalurie,  Gicht,  und  Steinkrankheiten.  Specielle  Pathologic  und 
Therapie  der  Stoffwechselkrankheiten.     German  transl.  by  S.  Hahn  (1880). 

•^  H.  Vogt.  Ein  Stoffwechselversuch  bei  acute  Gicht.  Deutsche  Arch,  fiir  khn.  Medizin, 
71,  21  (1900). 

'  R.  Fleischer.  Klinische  und  pathologisch-chemische  Beitrage  zur  Lehre  von  den 
Nierenkrankheiten.     Deutsche  Arch,  fiir  klin.  Medizin,  29,  129  (1881). 

*  T.  Futcher.  Some  Points  on  the  .Metabolism  in  Gout:  with  Special  Reference  to  the 
Relationship  between  the  L'ric  Acid  and  the  Phosphoric  Acid  Elimination  in  the  Interval 
and   during  Acute   .'Attacks.     Practitioner.   71,    181    (1903). 


288      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

blood  is  due  to  a  defect  in  the  power  of  the  kidneys  to  excrete  it. 
There  are  facts  which  make  it  seem  doubtful  if  there  is  a  connection 
between  gout  and  lead  poisoning.  Luthje  did  not  find  that  lead 
has  any  influence  on  the  excretion  of  uric  acid  after  thymus  feeding, 
or  that  there  is  any  indication  that  lead  poisoning  causes  a  reten- 
tion of  uric  acid  in  dogs.  Levison  ^  states  that  among  one  hundred 
and  sixty-three  cases  of  lead  intoxication  in  Frerich's  clinic  in  Ber- 
lin,, there  was  not  one  case  of  real  gout.  Roberts  ^  has  suggested  the 
name  uratosis  for  the  condition  in  which  urates  are  deposited  in 
the  body.  He  believes  that  gout  is  not  caused  b}^  lead  poisoning, 
but  that  gout  and  plumbism  are  two  different  conditions,  which 
have  uratosis  as  a  common  symptom.  Even  if  Roberts  is  right, 
it  is  still  possible  that  the  presence  of  uric  acid  in  the  blood  in 
these  conditions  is  due  to  an  imperfect  excretion  by  the  kidneys. 

The  question  of  the  relation  of  kidney  disease  to  lead  poisoning 
is  chiefly  a  clinical  one  yet,  and  we  would  not  profit  much  by  a 
discussion  of  it,  for  many  authors  assume,  with  Garrod,  that  a 
functional  disturbance  in  the  excreting  power  of  the  kidneys  pre- 
cedes gout  even  when  no  organic  changes  can  be  found.  It  is 
possible  that  those  inclined  to  gout  are  likewise  prone  to  kidney 
disease,  but  that  the  presence  of  uric  acid  in  the  blood  is  due  to 
entirely  different  reasons  in  the  two  cases. 

Stadthagen,^  von  Ackeren,*  Fodor,^  Albu,''  Magnus-Levy,^ 
Schreiber,^  Martin,^  and  Kaufmann  and  Mohr  ^^  have  found  the 

1  Levison.     Hirsch-Virchow's  Jahresb.  (1882),  2,  234. 

2W.  Roberts.  On  the  Deposition  of  the  Crystalline  Urates  in  the  Tissues  Considered 
as  a  Separate  Pathological  Incident,  with  a  Suggestion  for  a  Distinctive  Name.  Trans,  of 
the  Med.  Soc.  London,  14,  84  (1891). 

^Stadthagen.  Ueber  das  Vorkommen  von  Harnsaure  im  verscheidenen  thierischen 
Organen,  ihr  Verhalten  bei  der  Leukamie,  und  die  Frage  ihrer  Entstehung  aus  den  Stick- 
stoffbasen.     Virchow's  Archiv,  109,  390  (1887). 

■*v.  Ackeren.  Ueber  Harnsaureausscheidung  bei  einigen  Krankheiten,  insbesondere 
Morbus  Brighti.     Charity  Annalen,  17,  206  (1892). 

5  G.  Fodor.  Ueber  die  Rolle  der  Harnsaure  bei  Nephritis.  Centralblatt  fur  innere 
Medizin,  16,  865  (1895). 

6AIbu.  Discussion  of  Laquer's  Article.  Ueber  die  Ausscheidungsverhaltnisse  der 
Alloxurkorper  im  Harne  von  Gesunden  und  Kranken.  Verhandl.  des  14t  Kongr.  fiir  innere 
Medizin,  423  (1896). 

'  A.  Magnus-Levy.  Discussion  of  Laquer's  Article.  Ueber  die  Ausscheidungsver- 
haltnisse der  Alloxurkorper  im  Harne  von  Gesunden  und  Kranken.  Verhandl.  des  14t 
Kongr.  fur  innere  Medizin,  423  (1896). 

*  E.  Schreiber.  Ueber  die  Harnsaure  unter  physiologischen  und  pathologischen  Bed- 
ingungen.     Stuttgart  (1899). 

9  C.  Martin.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  bei  Nephritis. 
Centralblatt  ftir  innere  Medizin,  29,  625  (1899). 

10  M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologie 
der  Gicht.  H  Theil.  Ueber  Alloxurkorperausscheidung  unter  pathologischen  Verhaltnissen. 
Deutsche  Arch,  fur  klin.  Medizin,  74,  348  (1902). 


Pathology  289 

excretion  of  uric  acid  practically  the  same  in  nephritis  as  in  health, 
and  Ziilzer/  Vogel,^  and  Rommel  ^  have  found  it  even  high. 
Ka-ufmann  and  Mohr  ^  found  the  endogenous  uric  acid  normal  in 
nephritis. 

Kolisch  and  Dostal ''  and  Fodor  ^  by  use  of  the  erroneous  Krliger- 
Wulff  method,  found  the  purin  bases  high  and  uric  acid  low  in 
nephritis  as  in  gout.  By  use  of  more  accurate  methods,  Rommel,^ 
Zulzer,^  von  Noorden,''  Albu,^  Magnus-Levy,''  Ascoli,®  and  Martin^ 
found  the  quantity  of  purin  bases,  and  the  ratio,  uric  acid  :  purin 
bases,  normal  in  nephritis.  Rommel,  Schmoll,^"^  Weintraud," 
Kam,^2  and  Zagari  and  Pace  '^  have  found  that  excretion  of  uric 
acid  is  increased  after  thymus  feeding  in  nephritis. 

Minkowski  has  suggested  that  in  cases  where  uric  acid  is  found 
in  the  blood  a  high  content  of  the  blood  in  uric  acid  is  necessary 
to  excrete  this  compound. 

We  have  not  yet  enough  data  to  decide  in  favor  of  or  against 
the  theory  that  the  presence  of  uric  acid  in  the  blood  in  gout  is 
due  to  a  defect  in  the  power  of  the  kidneys  to  excrete  it.  We 
have  evidence  that  the  kidneys  can  excrete  fairly  large  quantities 
of  uric  acid  in  nephritis  and  in  gout.  In  gout,  and,  according  to 
Kam,  in  nephritis,  there  are  periods  when  the  excretion  of  uric 

1  G.  Ziilzer.  Ueber  die  Alloxvirkorperausscheidung  im  Ham  bei  Nephritis.  Berf.  klin. 
Wochenschrift,  33,  72  (1896). 

-  Vogel.  Krankheiten  der  Harnbereitenden  Organ.  Virchow's  Handbuch  der  spec. 
Path,  und  Ther.,  4,  2,  Erlangen  (1856-1865). 

3  O.  Rommel.  Die  Ausscheidung  der  Alloxurkorper  bei  Gicht  und  Schrumpfniere. 
Zeitschr.  fiir  klin.  Med.,  30,  200  (1896). 

*  M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorperfrage  und  zur  Pathologic 
der  Gicht.  II.  Theil.  Ueber  Alloxurkorperausscheidung  unter  physiologischen  Verhalt- 
nissen.     Deutsche  Arch,  fur  klin.  Medizin,  74,  348  (1902). 

'  R.  KoHsch  und  H.  Dostal.  Das  Verhalten  der  Alloxurkorper  in  pathologischen 
Harnen.     Wien.  klin.  Wochenschrift,  8,  413,  and  435  (1895). 

6  G.  von  Fodor.  Ueber  das  Verhalten  der  Harnsaure  bei  Nephritis.  Centralblatt  fiir 
innere  Medizin,  16,  865  (1895). 

'  von  Noorden,  Albu,  and  Magnus-Levy  in  a  Discussion  of  Laquer's  Article.  Ueber 
die  Ausscheidungsverhaltnisse  der  Alloxurkorper  im  Harne  von  Gesunden  und  Kranken. 
Verhandl.  des  14t  Kongr.  fur  innere  Med.,  420  (1896). 

^  G.  Ascoli.  Sul  comportamento  dei  corpi  allosurici  nelle  nefriti.  Clinica  Med.  (1898); 
Maly's  Jahresb.  tiber  die  Fortschritte  der  Thierchemie,  29,  722  (1899). 

^  C.  Martin.  Ueber  die  Ausscheidungsverhaltnisse  der  Alloxurkorper  bei  Nephritis. 
Centralblatt  fiir  innere  Medizin,  29,  625  (1899). 

1"  E.  Schmoll.  Stoffwechselversuch  an  einem  Gichtkranken.  Zeitschr.  fiir  klin.  Med., 
29,  510  (1896). 

1' Weintraud.  Zur  Entstehung  der  Harnsaure  im  Siiugethierorganismus.  Verhandl. 
des  14t  Kongr.  fiir  innere  Med.,  190  (1896). 

'2  B.  Kam.  Bijdrage  to  de  kenis  der  urinzuur-uitscheidung.  Leiden  (1898);  Maly's 
Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  28,  573  (1898). 

^3  G.  Zagari  e  D.  Pace.  La  genesi  dell'  acido  urico  e  la  gotta  in  riguardo  alia  patogenesi 
e  all'indirizzo  terapeutico.     Napoli  (1897).     Centralblatt  fiir  innere  Medizin,  19,  816  (1S9S). 


290      The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

acid  is  low  and  other  periods  when  it  is  not.  It  might  be  assumed 
that  there  is  a  retention  of  uric  acid  when  the  excretion  is  low. 
We  should  then  expect  to  find  uric  acid  in  gouty  blood  only  at  ' 
Such  a  period.  This  is  not  in  accord  with  the  fact  that  uric  acid 
has  been  found  in  the  blood  at  all  periods.  The  experiments  of 
Soetbeer  and  others  indicate  that  after  ingestion  of  purin  food 
the  excretion  of  uric  acid  is  not  increased,  or,  at  any  rate,  not  so 
much  as  in  health.  This  may  be  due  to  a  lack  of  absorption, 
to  the  fact  that  the  uric  acid  formed  is  oxidized  to  urea,  that  the 
nucleins  or  purin  bases  are  not  oxidized  to  uric  acid,  or  that  uric 
acid  is  formed,  but  is  retained  in  the  body  or  excreted  in  the  feces. 
Even  if  there  is  retention  of  uric  acid  in  gout,  it  is  plain  that  a 
retention  might  be  due  to  some  cause  other  than  diseased  kidneys. 
Minkowski  has  suggested  that  the  uric  acid  may  not  be  chemi- 
cally combined  in  such  a  way  as  to  be  in  a  condition  to  be  ex- 
creted, an  idea  suggested  by  Parkes  ^  long  ago. 

DECREASED  DESTRUCTION  OF  URIC  ACID 
The  old  theory  of  Liebig  ^  and  Jones  ^  was  that  uric  acid  is  an 
antecedent  of  urea  in  the  destructive  metabolism  of  proteid  by 
oxidation.  According  to  these  authors,  all  the  urea  excreted 
has  passed  through  the  stage  of  uric  acid.  If,  for  any  reason, 
the  oxidation  processes  of  the  body  become  defective,  more  of 
the  nitrogen  than  normally  is  oxidized  only  to  the  stage  of  uric 
acid,  and,  therefore,  less  uric  acid  is  excreted.  This  likewise  is 
the  theory  that  Ealfe  *  and  Cantani  ^  give  in  their  books. 

Even  more  recently,  Rendu,**  Murri,^  Stekel,*  and  Halliburton'' 
have  stated  that  the  formation  of  a  large  quantity  of  uric  acid 
is  due  to  a  diminution  of  the  oxidation  processes. 

1  E.  Parkes.  The  Composition  of  the  Urine  in  Health  and  Disease,  and  under  the 
Action  of  Remedies.     London  (1860). 

2  J.  Liebig.  Animal  Chemistry,  or  Organic  Chemistry  in  its  Application  to  Physiology 
and  Pathology.     Edited  by  W.  Gregory,  1843. 

3  H.  Bence  Jones.  Lectures  on  Some  of  the  Applications  of  Chemistry  and  Mechanics 
to  Pathology  and  Therapeutics.     London  (1867),  also 

A  Treatise  on  Gravel,  Calculus,  and  Gout.     London  (1845). 

^C.  Ralfe.     Outlines  of  Physiological  Chemistry.     London  (1873). 

5  Cantani.     Oxalurie,  Gicht  und  Steinkrankheiten.     Berlin  (1880). 

6  Rendu.  Goutte.  Dictionnaire  usual  des  sciences  medicales.  A.  Deschambre,  M. 
Duval,  et  L.  Lereboullet.     Paris  (1885),  706. 

^  Murri.  Uricamie  und  Gicht.  Kongr.  fiir  irmere  Med.  in  Rom.  Wien.  klin.  Wochen- 
schrift,  3,  316  (1890). 

*W.  Stekel.  Zur  Pathologic  und  Therapie  der  Gicht.  Wien.  klin.  Wochenschrift,  51, 
366,  418,  474,  518  (1901). 

'Halliburton.     Essentials  of  Chemical  Physiology  (1901). 


Pathology  291 

Murchison  ^  believes,  without  proof,  that  in  gout  there  is 
a  functional  derangement  of  the  liver  such  that  the  normal 
process  whereby  albuminous  matter  is  changed  to  urea  is  per- 
sistently deranged,  and  uric  acid  instead  of  urea  is  formed. 

Croftan,^  it  will  be  remembered,  showed  that  for  the  oxidation 
of  uric  acid  in  the  body  there  is  necessary  an  albuminose,  which 
seems  to  combine  with  the  uric  acid  and  bring  it  into  a  condition 
to  be  oxidized,  a  nucleo-proteid,  which  acts  as  an  oxidizing  agent, 
or  carrier  of  oxygen,  and  certain  inorganic  salts  to  hold  the 
albuminose  in  solution.  It  might  be  suggested  that  the  absence 
of  some  of  these  bodies  might  account  for  the  presence  of  an 
increased  amount  of  uric  acid  in  the  body. 

Kochmann  ^  thinks  that  when  the  liver  and  kidney  are  both 
diseased,  and  the  muscles  are  inactive  on  account  of  ver}^  little 
exercise,  uric  acid  may  accumulate  in  the  body  from  lack  of 
destruction,  for  it  seems  probable  that  uric  acid  is  destroyed 
chiefly  in  the  liver,  kidney,  and  muscles.  According  to  this 
author,  meat,  alcohol,  and  lead  lead  to  gout  by  causing  degen- 
eration in  the  liver  and  kidney. 

According  to  Klemperer,*  gouty  blood  destroys  uric  acid  to 
about  the  same  extent  as  healthy  blood.  Experiment  seems  to 
show,  however,  that  the  blood  itself  is  an  unimportant  agent  in  the 
oxidation  of  uric  acid. 

Ten  Gate  ^  fed  uric  acid  to  a  gouty  patient,  but  did  not  find 
that  it  gave  increased  excretion  of  uric  acid.  He  concluded  that 
the  uric  acid  is  destroyed  as  well  in  gout  as  in  health.  There  was 
no  evidence  that  the  uric  acid  was  absorbed  in  the  experiment 
of  ten  Gate. 

Wiener,'^  Rosin,^  and  Kionka  ^  are  likewise  of  the  opinion  that 
the  presence  of  uric  acid  in  the  blood  in  gout  may  be  due  to 

1  G.  Miirchison.     Clinical  Lectures  on  Diseases  of  the  Liver.     3d  ed.,  568  (1877). 

2  A.  Croftan.  Synopsis  of  Experiments  on  the  Transformation  of  Circulating  Uric  Acid 
in  the  Organism  of  Man  and  Animals.     Med.  Record,  64,  6  (1903). 

3  M.  Kochmann,  Ueber  Fleischnahrung  and  ihre  Beziehung  zur  Gicht.  Pfliiger's 
Archiv.  fur  die  gesammt.  Physiol.,  94,  593  (1903). 

*  G.  Klemperer.  Losung  und  Zerstorung  der  Harnsaure  im  Blute  Gesunden  und 
Gichtkranken.     Therapie  der  Gegenwart,  Neue  Folge,  3,  344  (1901). 

■''  B.  ten  Gate.     Beitrage  zur  gichtischer  Diathese.     Inaug.  Dissert.,  Gottingen  (1899). 

^  H.  Wiener.  Ueber  Zersetzimg  und  Bildung  von  Harnsaure  in  Thierkorper.  Arch, 
fiir  exp.  Path.  u.  Pharm.,  42,  375  (1899). 

^  H.  Rosin.  LTeber  den  Augenblicklichen  Stand  der  Lehre  von  der  Gicht.  Therapeut- 
ische  Monatshefte,  15,  168  (1901). 

*  H.  Kionka.  Entstehung  und  Wesen  der  Vogelgicht  und  ihre  Beziehung  zur  Arthritis 
urica  des  Menschen.     Arch,  fiir  exp.  Path.  u.  Pharm.,  44,  186  (1900). 


292      The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

decreased  destruction  of  uric  acid.  Decreased  destruction  of  uric 
acid  cannot  be  the  sole  cause  of  the  presence  of  uric  acid  in  the 
blood.  A  decreased  destruction  of  uric  acid  would  lead  merely  to 
an  increased  excretion  of  uric  acid.  There  is  not  an  increased 
excretion  of  uric  acid  in  gout,  nor  is  there  any  other  evidence  of 
an  increased  formation  of  uric  acid. 

CHEMICAL  CHANGE  IN  THE  URIC  ACID 

Pfeiffer/  it  will  be  remembered,  found  that  the  uric  acid  in 
the  urine  in  gout  is  in  what  he  called  the  ^'  free  "  condition.  By 
this  he  meant  that  it  was  easily  given  up  to  the  uric  acid  filter. 
He  assumed  by  analogy  that  the  uric  acid  is  "  free  "  in  the  blood 
in  gout,  and  that  this  is  why  it  is  found  on  analysis  and  why  it 
is  easily  given  up  in  the  joints  to  form  concretions.  We  have 
already  seen  the  explanation  of  Pfeiffer's  peculiar  results.  The 
foundation  of  his  theory  is  wrong. 

It  is  plain  that  the  data  we  have  at  present  are  not  sufficient  to 
enable  us  to  explain  the  cause  of  the  presence  of  uric  acid  in  the 
blood  in  gout. 

Cause  of  the  Formation  of  the  Uric  Acid  Concretions  in  Gout 

CHEMICAL   THEORIES 

Pearson,^  Wollaston,^  Fourcroy,*  Holland,^  and  Cruveilhier  ^ 
all  regarded  uric  acid  as  intimately  connected  with  gout.  Forbes  ^ 
and  Parkinson  ^  went  further,  and  stated  their  belief  that  when 
the  system  or  blood  has  so  much  uric  acid  in  it  that  it  has  become 
saturated,  a  precipitation  of  this  body  in  the  joints  takes  place, 

1  E.  Pfeiffer.  Harnsaureausscheidung  und  Harnsaurelosung.  Verhandl.  des  7t  Kongr. 
fiir  innere  Medizin,  327  (1888). 

Ihid.  Die  Natur  und  Behandlung  der  Gicht.  Verhandl.  des  St  Kongr.  fiir  innere 
Medizin,  166  (1889). 

Ihid.     Die  Gicht  und  ihie  erfolgreich  Behandlung.     Wiesbaden' (1891),  2d  ed. 

Ihid.  Ueber  Harnsaure  und  Gicht.  Berl.  klin.  Wochenschrift,  29,  383,  412,  461,  490, 
536  (1892). 

2  G.  Pearson.     Philosophical  Transactions  (1797),  pt.  2. 

^Wollaston.  On  Gouty  and  Urinary  Concretions.  Philosophical  Transactions,  2,  386 
(1797). 

■*  Foiu'croy.  Examen  des  experiences  et  des  observations  nouvelles  de  M.  G.  Pearson, 
etc.     Annales  de  Chimie,  27,  225  (1798). 

5  H.  Holland.     Medical  Notes  and  Reflexions  (1839). 

*  Cruveilhier.     Anatomic   pathologique.     Paris   (1829). 

^  M.  Forbes.     A  Treatise  on  Gravel  and  Gout.     London  (1793). 

^  J.  Parkinson.     Observations  on  the  Nature  and  Cure  of  Gout.     London  (1805). 


Pathology  293 

causing  gout.  Mazuyer/  Andral,^  Copeland,^  Rayer/  and  Ure  •"' 
all  believed  that  in  gout  the  precipitation  of  uric  acid  in  the  joints 
is  due  to  the  fact  that  the  blood  is  saturated  with  it. 

Andral  and  Copeland  believed  that  the  presence  of  the  uric  acid 
was  due  to  meat  eating.  Copeland  suggested  that  the  kidneys 
are  unable  to  excrete  the  excessive  amount  of  uric  acid.  Mazuyer 
recommended  alkalies  for  dissolving  the  concretions.  Liebig  ® 
and  Jones  ^  had  likewise  believed  that  gout  is  due  to  the  presence 
of  an  increased  amount  of  uric  acid  in  the  system. 

Toward  the  end  of  the  seventeenth  century,  Sydenham  had 
stated  his  belief  that  there  was  a  "materia  peccans  "  circulating 
in  the  blood  in  gout  which  caused  the  disease.  The  greater  part 
of  the  physicians  for  the  next  century  and  a  half  accepted  Syden- 
ham's belief.  It  was  this  belief,  together  with  the  discovery  of 
the  presence  of  uric  acid  in  the  joints,  that  led  to  the  idea  that 
uric  acid  is  the  circulating  "  materia  peccans."  But,  imtil  the 
work  of  Garrod,  there  was  no  proof  that  there  is  uric  acid  in  the 
blood  in  gout.  Todd,^  indeed,  writing  a  few  years  before  Garrod 's 
discovery,  stated  that  there  is  probably  a  morbid  matter  circu- 
lating in  the  blood,  but  criticised  Liebig 's  view  that  it  is  uric 
acid. 

In  view  of  the  belief  of  his  contemporaries  concerning  the  con- 
nection of  uric  acid  and  gout,  it  is  easy  to  understand  how  im- 
portant the  discovery  of  Garrod,*  that  uric  acid  is  present  in  the 
blood  in  gout  and  that  gout  and  kidney  disease  are  often  asso- 
ciated, appeared.  According  to  Garrod,^"  the  primary  defect  in 
gout  is  a  failure  on  the  part  of  the  kidnej's  to  excrete  uric  acid, 
which  then  becomes  stored  up  in  the  blood.  When,  through  a 
decrease   in  alkalinity,   the  blood  becomes  saturated   with  uric 

1  Mazuyer.  Acetate  d'ammoniaque  employe  centre  I'ivresse.  Arch.  gen.  de  m^d., 
1  ser..  Vol.  II,  132  (1826). 

2  G.  Andral.     Precis  d'anatomie  pathologique.     Paris  (1829). 

^Copeland.     Dictionary  of  Practical  Medicine  (1834),  Vol.  I,  Article  on  Blood. 

*P.  Rayer.     Traite  des  maladies  des  Reins.     Paris  (1839),  Vol.  I. 

■■'  A.  Ure.     Researches  on  Gout.     Med.  Gazette,  35,  188  (1844). 

6  J.  Liebig.  Animal  Chemistry,  or  Organic  Chemistry  in  Its  App  ication  to  Physiology 
and  Pathology.     Edited  by  W.  Gregory  (1843). 

'  H.  Bence  Jones.  Lectures  on  Some  of  the  Applications  of  Chemistry  and  Mechanics 
to  Pathology  and  Therapeutics.     London  (1867) ;  also 

A  Treatise  on  Gravel,  Calculus,  and  Gout.     London  (1845). 

*  R.  Todd.  Practical  Remarks  on  Gout,  Rheumatic  Fever,  and  Chronic  Rheumatism  of 
the  Joints  (1843).     (The  Croonian  Lecture  for  1843.) 

^  A.  Garrod.  Observations  on  Certain  Pathological  Conditions  of  the  Blood  and  Urine 
in  Gout,  Rheumatism,  and  Bright's  Disease.     Medico-Chirurg.  Trans..  31,  S3  (1848). 

^0  A.  Garrod.   The  Nature  and  Treatment  of  Gout  and  Rheumatic  Gout.   London  (1859) 


294      The  Chemistry ,  Physiology ,  and  Pathology  of  Uric  Acid 

acid,  this  body  precipitates  in  the  joints.  According  to  Garrod, 
uric  acid  is  the  cause  of  gout.  Garrod  bases  his  theory  on  several 
assumptions:  (a)  Gout  is  always  preceded  by  kidney  disease; 
(h)  the  excretion  of  uric  acid  is  low  in  gout;  (c)  the  blood  is 
saturated  with  uric  acid  in  gout;  (d)  the  alkalinity  of  the 
blood  is  decreased  in  gout;  (e)  the  solubility  of  sodium  acid 
urate  in  the  blood  decreases  as  the  alkalinity  of  the  blood 
decreases. 

We  have  seen  that  it  has  not  been  proved  that  gout  is  always 
preceded  by  kidney  disease.  We  know  that  the  excretion  of  uric 
acid  is  not  low  in  gout  or  in  kidney  disease,  that  the  blood  is  not 
nearly  saturated  with  uric  acid  in  gout,  that  a  decrease  in  the 
alkalinity  of  the  blood  does  not  decrease  its  power  of  dissolving  uric 
acid,  and  that  the  alkalinity  of  the  blood  is  not  decreased  in  gout. 
That  Garrod 's  explanation  of  gout  is  true  is  doubtful  in  view  of  the 
fact  that  uric  acid  is  present  in  the  blood  not  only  in  nephritis  and 
gout,  but  also  in  pneumonia,  leukemia,  and  other  diseases  which  ap- 
pear to  have  no  relation  to  gout.  But  five  cases  ^  of  the  occurrence 
of  both  gout  and  leukemia  in  the  same  person  have  been  reported; 
two  by  Duckworth,  and  one  each  by  Pribram,  Miiller,  and  Spitzer. 
Neumeister,^  in  a  statement  which  he  attributes  to  von  Noorden, 
says,  "  The  idea  that  presence  and  solution  of  gout  is  depend- 
ent on  alkalinity  of  the  blood  is  as  much  probable  as  to  think  that 
alcoholic  drinks  can  dissolve  the  fat  of  the  tissues,  acid  the  calcium 
of  the  osteophytes  and  trichina  capsule,  or  that  through  oyster 
shells  a  carcinoma  can  be  calcified,  or  that  by  drinking  of  a  dilute 
solution  of  FeClg  we  can  stop  the  bleeding  of  an  artery.  Besides, 
we  know  clinically  the  immunity  of  gouty  nodules  to  alkalies. 
The  results  of  both  physicians  do  not  affect  these  conclusions 
since  even  homeopaths  get  clinical  cures."  Roberts  ^  states  that 
he  has  seen  gouty  attacks  recur  when  the  urine  has  been  kept 
persistently  alkaline  for  a  long  time.  Further,  as  Barclay  * 
pointed  out,  we  have  urate  concretions  that  cause  no  pain  or 
inflammation,  and  there  is  a  gouty  gastritis  and  gouty  bronchitis 
which  is  not  associated  with  urate  crystals  in  the  affected  parts. 

1  O.  Minkowski.  Die  Gicht.  Specielle  Pathologie  und  Therapie  von  Nothnagel,  VII, 
Theil  III,  Wien  (1903),  p.  212. 

2R.  Neumeister.     Lehrbuch  der  physiol.  Chem.,  Part  2,  p.  251,  Jena  (1895). 

'W.  Roberts.  On  the  Chemistry  and  Therapeutics  of  Uric  Acid,  Gravel,  and  Gout. 
(Croonian  Lectures  for  1892.)    Lancet  (1892),  I,  1345,  1399,  and  II,  69,  127. 

*  A.  Barclay.  On  Gout  and  Rheumatism  in  Relation  to  Disease  of  the  Heart.  London 
(1866). 


Pathology  295 

Gardner  *  and  Hood  ^  long  ago  suggested  that  the  uric  acid  in 
the  blood  may  be  a  symptom  of  gout  and  not  the  cause  of  it. 

Lecorche,^  Charcot,"*  and  Levison  ^  maintain  with  Garrod  that 
gout  is  due  to  the  presence  of  excess  of  uric  acid  in  the  blood. 

Haig  *•  has  proposed  a  very  simple  theory  for  the  explanation 
not  only  of  gout  but  of  various  other  diseases.  According  to  this 
author,  if  the  blood  is  strongly  alkaline,  the  uric  acid  formed 
from  the  food  is  kept  in  solution  and  excreted.  If  the  blood  is 
only  slightly  alkaline,  the  uric  acid  is  precipitated  in  the  joints  and 
causes  gout  or  rheumatism.  The  presence  of  uric  acid  in  the  blood 
causes  all  sorts  of  symptoms  and  diseases,  according  to  Haig. 

Haig  has  done  a  little  experimental  work  on  Vv'hich  he  bases  his 
theories,  but  from  a  small  number  of  experiments,  and  by  the 
aid  of  a  good  many  unproved  assumptions  and  doubtful  logic,  he 
has  built  up  a  very  comprehensive  theory.  There  is  no  need  of 
criticising  his  work  in  detail,-  however.  The  experiments  and 
chief  assumptions  on  which  he  bases  his  whole  theory  are  open 
to  criticism.  In  speaking  of  increased  or  decreased  excretion  of 
uric  acid,  he  refers  to  an  increase  or  decrease  in  the  ratio  of  the 
quantity  of  uric  acid  to  the  quantity  of  urea  in  the  urine.  We 
have  seen  that  the  value  of  this  ratio  has  no  meaning,  that  the 
quantity  of  uric  acid  and  urea  in  the  urine  can  be  independently 
varied  at  will  by  regulating  the  diet  without  affecting  the  health. 
He  has  used  inaccurate  methods  for  the  determination  of  uric 
acid  and  urea  throughout  this  work.  He  has  assumed  that  the 
quantity  of  uric  acid  in  the  urine  varies  inversely  as  the  acidity 
of  the  urine,  that  the  alkalinity  of  the  blood  can  be  directly  varied 
by  alkalies  and  acids  given  in  the  food,  that  the  solubility  of 
sodium  acid  urate  in  the  blood  varies  with  the  alkalinity  of  the 
blood,  —  things  we  know  to  be  untnie,  —  and  that  the  rate  of 

iW.  Gardner.  On  Gout:  Its  History,  Its  Causes,  and  Its  Cure.  4th  ed.,  London 
(1860). 

2  P.  Hood.     A  Treatise  on  Gout,  Rheumatism,  and  Allied  Afifections.     London  (1871). 

3  Lecorch^.     Traits  theorique  et  practique  de  la  goutte.     Paris  (1884). 

*  J.  Charcot.  Legons  siu-  les  maladies  du  foie  des  voies  bUiaires  et  des  reines.  Paris 
(1877). 

^  F.  Levison.  Zur  Behandlung  der  Gicht  (Arthritis  urica)  und  speciell  von  der  Behand- 
lung  der  chronischen  Formen  dieser  Krankheit.  St.  Petersburg  med.  Wochenschrift, 
Neue  Folge,  14,  Nos.  1  and  9  (1897),  and 

Ibid.  Zur  Lehre  von  der  Pathogenese  der  Gicht.  Zeitschr.  fur  klin.  Med.,  26,  293 
(1894),  and 

Ihid.  The  Uric  Acid  Diathesis:  Gout,  Sand,  and  Gravel.  Transl.  by  L.  Scott,  Lon- 
don (1894). 

«  A.  Haig.     Uric  Acid  as  a  Factor  in  the  Causation  of  Disease.      3d  ed..  Phila.  (1896). 


296      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

the  circulation  of  the  blood  in  the  capillaries  is  dependent  on  the 
quantity  of  uric  acid  in  the  blood  —  something  for  which  there  is 
no  foundation.    None  of  his  conclusions,  therefore,  are  of  any  value. 

Luff's^  theory  is  similar  to  that  of  Garrod  in  a  general  way. 
He  assumes  ttiat  kidney  disease  always  precedes  an  attack  of  gout. 
The  kidneys  both  form  and  excrete  uric  acid.  When  they  are 
diseased  the  uric  acid  formed  is  reabsorbed  by  the  blood.  It  cir- 
culates in  the  blood  as  a  quadriurate  which  easily  changes  to  a 
soluble  gelatinous  form  of  biurate.  If  this  gelatinous  biurate  is 
not  rapidly  excreted,  it  changes  to  the  insoluble  crystalline  biurate. 
A  decrease  in  the  alkalinity  of  the  blood  does  not  affect  the  solu- 
bility of  the  urate. 

It  has  not  been  proved  that  kidney  disease  always  precedes 
gout.  Luff  does  not  offer  sufficient  evidence  to  show  that  uric 
acid  is  formed  in  the  kidneys.  We  know  that  the  quadriurate 
does  not  exist,  and  we  know  that  the  blood  is  not  saturated  with 
uric  acid  in  gout.     Luff's  theory,  therefore,  cannot  be  correct. 

According  to  Ebstein,^  uric  acid  circulates  in  the  blood  as  a 
neutral  urate.  In  gout  there  is  an  increased  formation  of  uric 
acid  in  perverse  places,  such  as  the  muscles,  cartilage,  and  bone 
marrow.  When  for  some  reason  there  is  a  stasis  of  the  blood  or 
lymph  stream  containing  an  increased  quantity  of  urate,  there 
occurs  an  infiltration  of  the  tissues  in  the  circumscribed  area  by 
the  lymph  containing  the  dissolved  urate.  This  compound  is  a 
poison  and  causes  necrosis  of  the  surrounding  tissue.  In  the 
process  of  necrosis  a  free  acid  is  formed  which  changes  the  neutral 
urate  to  insoluble  acid  urate  and  this  latter  precipitates  out. 
Schreiber,^  who  repeated  the  experiments  of  Ebstein,  and  appa- 
rently confirmed  them,  agrees  with  Ebstein. 

1  A.  Lufif.  The  Chemistry  and  Pathology  of  Gout.  (Goulstonian  Lectures.)  Lancet 
(1897),  I,  857,  942,  and  1069. 

Jbid.     The  Pathology  and  Treatment  of  Gout.     Brit.  Med.  Journ.  (1898),  1,  150. 

Ibid.     Gout:    Its  Pathology  and  Treatment.     New  York  (1899). 

Ibid.  The  Gelatinous  Form  of  Sodium  Biurate  and  Its  Bearing  on  the  Pathology  and 
Treatment  of  Gout.     Brit.  Med.  Journ.  (1899),  II,   1163. 

Ibid.  The  Gelatinous  Form  of  Sodium  Biurate  and  Its  Bearing  on  the  Pathology  and 
Treatment  of  Gout.     Brit.  Med.  Journ.  (1900),  I,  836. 

^  W.  Ebstein.  The  Regimen  to  be  Adopted  in  Cases  of  Acute  Gout.  Transl.  by  Scott, 
London  (1885),  and 

Ibid.     Beitrage  zur  Lehre  von  der  harnsauren  Diathese.     Wiesbaden  (1891). 

3  E.  Schreiber.  Gicht.  Ueber  die  Harnsaure  unter  physiologischen  und  pathologischen 
Bedingungen.     Stuttgart  (1899),  and 

E.  Schreiber  und  Zaudy.  Ueber  die  bei  Vogeln  kunstlich  zu  erzeugenden  Harnsaure- 
Ablagerungen.     Pfliiger's  Archiv,  79,  53  (1900). 


Pathology  297 

Neutral  urates  exist  only  in  solutions  which  are  strongly  alka- 
line, with  such  a  base  as  NaOH.  They  cannot  exist  in  a  solution 
containing  carbonates.  Ebsteiu  is,  therefore,  wrong  in  believing 
that  uric  acid  exists  in  the  blood  as  neutral  urate.  There  is  no 
proof  that  in  gout  there  is  a  formation  of  uric  acid  in  anomalous 
places.  The  stasis  and  infiltration  of  surrounding  tissue  assumed 
by  Ebstein  is  not  at  all  proved.  Experiment  shows  that  uric 
acid  and  acid  urates  are  not  toxic,  or  are  only  very  slightly  toxic. 
We  cannot  assume  that  the  small  quantity  present  in  the  blood 
in  cases  of  gout  can  produce  a  necrosis.^  We  know  that  just 
before  an  attack  of  gout  there  are  no  apparent  toxic  symptoms, 
although  the  blood  contains  uric  acid.^  Sodium  acid  urate,  the 
form  in  which  uric  acid  is  found  in  gouty  concretions,  cannot 
exist  in  the  presence  of  a  free  acid.  It  is  changed  to  uric  acid. 
Further,  the  evidence  seems  to  show  that  the  tissue  change  is  not 
a  process  of  necrosis.  Mordhorst  ^  found  that  the  modified  tissue 
—  degenerated  tissue,  according  to  this  author  —  reacts  not  acid 
but  alkaline.  Finally,  we  have  sufficiently  good  evidence  to  show 
that  the  urate  deposits  in  healthy  tissue.  The  truth  of  all  these 
statements  has  been  shown  in  earlier  parts  of  this  work.  Ebstein's 
theory  must,  therefore,  be  almost  entirely  wrong. 

A  part  of  these  objections  apply  also  to  the  theories  of  Klem- 
perer  ^  and  von  Noorden/  for  both  of  these  authors  assume  that 
the  necrosis  precedes  the  deposition  of  the  urate  in  gout.  Ac- 
cording to  Klemperer,  the  necrosis  is  due  to  some  unknown 
"  gichtstoff."  According  to  von  Noorden,  the  formation  and 
deposition  of  the  urate  is  due  to  the  activity  of  a  ferment. 

Mordhorst  ^  believes  that  uric  acid  circulates  in  the  form  of  a 
suspension  of  "  kugel  "  urates  containing  variable  quantities  of 
alkali.  In  gout  the  quantity  of  urate  in  the  blood  is  increased 
and  the  alkalinity  and  the  temperature  decreased.  These  condi- 
tions lead  to  a  precipitation  of  the  spherical  or  amorphous  urates 

1  G.  Klemperer.  Zur  Pathologie  und  Therapie  der  Gicht.  Vortrag  in  der  Verein  fiir 
innere  Med.  zu  Berl.     Deutsche  med.  Wochenschrift,  21,  655  (1895). 

2  F.  Levison.  The  Uric  Acid  Diathesis:  Gout,  Sand,  and  Gravel.  Transl.  by  L.  Scott. 
London   (1894). 

3  Mordhorst.  Zur  Entstehung  der  Uratablagerung  bei  Gicht.  Virchow's  Archiv,  148, 
285  (1897). 

*  C.  V.  Noorden.     Lehrbuch  der  Pathologie  des  Stoffwechsels.     Berlin  (1893). 

^  C.  Mordhorst.  Zur  Pathologie  der  Gicht.  Verhandl.  des  14t  Kongr.  fiir  innere 
Medizin,  (1896),  405,  also 

Ibid.  Die  Entstehung  und  Auflosung  Harnsaureverbindungen  ausserhalb  und  innerhalb 
des  menschlichen  Korpers.     Zeitschr.  fiir  klin.  Med.,  22,  65  (1897). 


298      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

which  gradually  become  crystalline.  The  precipitation  takes 
place  in  the  cartilage  on  account  of  the  fact  that  the  blood  supply 
is  poor,  and  the  cartilage  is  therefore  nourished  chiefly  by  osmosis. 
Acids  and  acid  salts  diffuse  more  rapidly  than  alkalies  or  alkaline 
salts. 

We  have  seen  that  urates  such  as  Mordhorst  speaks  of,  con- 
taining a  variable  quantity  of  alkali,  do  not  exist,  that  the  alka- 
linity of  the  blood  is  not  decreased,  and  that  the  blood  is  not 
saturated  with  uric  acid  in  gout. 

We  have  already  seen  that  Kolisch,^  and  more  recently  Croftan,^ 
are  in  error  in  their  view  that  the  fault  in  gout  lies  in  formation 
of  too  little  uric  acid  and  too  large  quantity  of  toxic  purin  bases. 

According  to  Pfeiffer,^  the  uric  acid  in  the  blood  in  gout  is  in 
such  a  condition  that  it  easily  precipitates,  just  as  the  uric  acid 
easily  precipitates  from  the  urine  in  gout.  This  author  believes 
that  the  uric  acid  deposits  only  in  tissue  which  is  necrosed. 

We  must  remember,  as  Liebreich  *  pointed  out,  that  the  deposit 
in  the  joints  is  not  uric  acid  as  in  urine,  but  sodium  acid  urate. 
Further,  we  have  seen  that  Pfeiffer's  experimental  work  is  open 
to  criticism,  and  the  conclusions  he  drew  from  his  work  were 
erroneous.  Finally,  necrosis  does  not  precede  the  formation  of 
the  urate  concretions. 

Roberts  ^  called  attention  to  the  fact  that  the  tissues  in  which 
the  urate  deposits  are  chiefly  found,  the  cartilage,  ligaments, 
and  tendons,  and  the  synovia  in  which  these  tissues  are  bathed, 
are  richer  in  sodium  salts  than  other  parts  of  the  body.     We  know 

*  R.  Kolisch.  Ueber  Wesen  und  Behandlung  der  Gicht.  Wien.  klin.  Wochenschrift,  8, 
787  (1895),    also 

Ueber  Wesen  und  Behandlung  der  uratischen  Diathese.     Stuttgart  (1895),  and 

R.  Kolisch  und  Dostal.  Das  Verhalten  der  Alloxurkorper  im  pathologischen  Harn. 
Wien.  klin.  Wochenschrift,  8,  413,  and  435  (1895). 

^  A.  Croftan.  An  Investigation  into  the  Causes  of  So-Called  Uric  Acid  Lesions  and  a 
Rational  Therapeutics  of  the  Uratic  Diathesis.      N.  Y.  Med.  Journ.,  72,  221  (1900). 

^  E.  Pfeiffer.  Harnsaureausscheidung  und  Harnsaurelosung.  Verhandl.  des  7t  Kongr. 
fiir  innere  Medizin,  Wiesbaden  (1886),  444. 

Ibid.     Die   Natur   und  Behandlung   der   Gicht.      Verhandl.   des  8t  Kongr.   fiir  innere 
Medizin  (1889),   166. 
'    Ibid.     Die  Gicht  und  ihre  erfolgreich  Behandlung.     Wiesbaden  (1891),  2d  ed. 

Ibid.  Ueber  Harnsaure  und  Gicht.  Berl.  klin.  Wochenschrift,  29,  383,  412,  461.  490, 
and  .5.36  (1892). 

Ibid.  Ueber  die  Ausscheidung  im  Urin  wahrend  des  acuten  Gichtanfalles  mit  besond- 
erer  Beriicksichtigung  der  Harnsaure.       Berl.  klin.  Wochenschrift,  33,  319  (1896). 

•*  Liebreich.  In  Discussion  of  Article  by  Pfeiffer.  Harnsaureausscheidung  und  Harn- 
saurelosung.    Verhandl.  des  17t  Kongr.  fiir  innere  Medizin,  337  (1888). 

■'' W.  Roberts.  On  the  Chemistry  and  Therapeutics  of  L^^ric  Acid,  Gravel,  and  Gout. 
(Croonian  Lectures  for  1892.)     Lancet  (1892),  I,  1345,  1399,  and  II,  69,  127. 


Pathology  299 

that  the  presence  of  sodium  salts  decreases  the  solubility  of  sodium 
acid  urate.  According  to  Roberts,  the  synovia  becomes  satu- 
rated with  sodium  acid  urate  at  a  much  lower  concentration  of 
urate  than  the  blood,  and  precipitates  in  the  surrounding  tissue. 
He  found  the  synovia  of  stall-fed  animals  who  got  little  exercise 
much  richer  in  sodium  salts  than  that  of  animals  that  had  plenty 
of  exercise,  and  thought  the  fact  might  be  of  some  importance  in 
the  etiology  of  gout.  Experiment  showed  that  if  the  tarsal 
bones  of  a  pig  are  immersed  in  a  solution  of  sodium  acid  urate,  a 
deposition  of  crystals  of  sodium  acid  urate  in  the  substance  of 
the  tissue  takes  place.  The  crystals  are  firmly  imbedded  and 
cannot  be  removed  by  rubbing  with  a  nail  brush.  Freudweiler  ^  is 
inclined  to  think  that  the  salts  may  cause  the  precipitation  of  urates. 

We  know  that  Roberts  is  wrong  in  his  belief  that  uric  acid 
exists  in  the  blood  as  quadriurate,  and  that  this  changes  to  the 
biurate  and  precipitates  in  gout,  for  we  have  seen  that  the  quad- 
riurate does  not  exist.  We  have  no  direct  evidence  that  Roberts 
is  wrong  in  his  belief  that  the  formation  of  concretions  is  due 
to  a  precipitation  from  a  saturated  solution.  But  here  again  comes 
up  the  question  of  why  there  are  no  urate  concretions  in  cases  of 
leukemia,  pneumonia,  etc.,  where  the  blood  contains  uric  acid. 

Various  other  theories,  or  rather  guesses  without  any  experi- 
mental basis,  have  been  offered  concerning  the  cause  of  the  forma- 
tion of  gouty  concretions.  Thus,  according  to  Ewich,^  the  uric 
acid  circulates  in  the  blood  as  such.  It  sometimes  reacts  with 
the  NazCOg  to  form  sodium  acid  urate,  and  this  urate  precipitates 
in  the  joints.  According  to  this  theory,  sodium  acid  urate  must 
be  less  soluble  than  uric  acid,  something  we  knew  to  be  untrue. 
According  to  Ritter,^  an  increase  in  the  acid  sodium  phosphate  in 
the  blood  will  bring  about  a  precipitate  of  sodium  acid  urate. 
We  know  that  this  cannot  be  so  even  if  we  assume  that  the  acid 
phosphate  is  not  neutralized.  Ritter  drew  his  conclusions  from 
his  experiments  on  the  urine  where  the  precipitate  is  uric  acid  and 
not  urate.  According  to  Bunge,^  the  uric  acid  may  circulate 
in  the  blood  as  an  easily  soluble  compound  with  some  organic 

'  M.  Freudweiler.  Experimentelle  Untersuchungen  iiber  die  Entstehung  der  Gicht. 
Deutsche  Arch,  fur  khn.  Medizin,  68,  155  (1900). 

2  Ewich.  Die  Natur  und  Behandlung  der  Gicht  auf  dem  8t  Kongr.  fiir  innere  Medizin, 
Nebst  Bemerkungen  zum  Correferat.     Deutsche  med.  Wochenschrift,  15,  774  (1889). 

■'  A.  Ritter.  Ueber  die  Bedingungen  fiir  die  Entstehung  der  Harnsedimente ;  ein  Beitrag 
zur  Theorie  der  Gicht.     Zeitschr.  fiir  Biol.,  35,  155  (1897). 

^  Bunge.     Lehrbuch  der  physiologischen  und  pathologi.schen  Chemie.     Leipzig  (1902'). 


300      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

substance.  This  compound  may  be  broken  up  in  the  organism 
by  a  ferment  in  gout  and  give  the  urate.  Bowlby  ^  thinks  that 
the  urate  concretions  come  from  a  disintegration  of  the  cartilage 
itself,  and  Roose  ^  that  they  are  due  to  a  functional  disorder  of 
the  liver.     These  are,  of  course,  merely  guesses. 

Gore  ^  and  Hutchinson  ^  believe  that  gout  is  an  autointoxica- 
tion due  to  poisons  formed  in  the  alimentary  canal.  We  know 
that  there  are  digestive  disturbances  in  gout,  and  there  are  indi- 
cations of  intestinal  fermentation.  Hutchinson  *  states  that 
the  uric  acid  comes  from  the  destruction  of  leucocytes  which  are 
formed  in  large  quantities  to  repel  some  toxic  action. 

Minkowski  ^  states  that  we  can  probably  conclude  that  there  is 
abnormal  nuclein  metabolism;  whether  of  exogenous  or  endoge- 
nous nuclein  we  cannot  say.  It  is  possible,  according  to  him,  that 
the  uric  acid  formed  from  the  nuclein  is  not  combined  in  such  a 
way  that  it  can  properly  pass  through  the  body  and  undergo  its 
normal  metabolism. 

NERVOUS  THEORIES 

From  the  time  of  Stahl,  w^ho  was  a  contemporary  of  Sydenham, 
there  have  been  physicians  who  have  believed  that  the  humoral 
theories  are  wrong  and  that  gout  is  a  disease  of  nervous  origin. 
In  the  present  century,  CuUen,^  Wells,''  Liveing,*  Ord,^  Paget, ^° 
Meldon,"  Latham,^^  Ewart,^^  and  Duckworth"  have  emphasized 

I  A.  Bowlby.     Surgical  Pathology  and  Morbid  Anatomy.     London  (1887). 

^  R.  Roose.  Gout  and  Its  Relation  to  Diseases  of  the  Liver  and  Kidneys.  London 
(1887),  3d  ed. 

3  W.  Gore.     The  Origin  of  Gout.     Brit.  Med.  Journ.  (1900),  II,  898. 

*  W.  Hutchinson.     The  Meaning  of  Uric  Acid  and  the  Urates.      Lancet  (1903),  I,  288. 

'  O.  Minkowski.  Die  Gicht.  Nothnagel's  Specielle  Pathologie  und  Therapie.  Bd. 
VII,  Th.  Ill  (1903),  Wien. 

6W.  Cullen.     First  Lines  of  Practice  of  Physic,  Vol.  II,  Chap.  14,  Phila.  (1861). 

^  S.  Wells.     Practical  Observations  on  Gout,  etc.  (1859). 

'  E.  Liveing.     On  Megrim,  Sick  Headache,  and  Some  Allied  Disorders.     London  (1873). 

»  Ord.  On  the  Relation  of  Gout  to  Uric  Acid.  St.  Thomas's  Hospital  Reports,  3,  227 
(1873). 

'"J.  Paget.     Clinical  Lectures  and  Essays.     London  (1875) 

II  A.  Meldon.     Pathology  and  Treatment  of  Gout.     Brit.  Med.  Journ.  (1881),  I,  466. 

'-  P.  Latham.  Some  Points  on  the  Pathology  of  Rheumatism,  Gout,  and  Diabetes. 
(Croonian  Lectures.)     Lancet  (1886).  I,  626,  673,  723,  771,  and  817. 

i^W.  Ewart.     Gout  and  Goutiness  and  Their  Treatment.     London  (1896). 

i<  D.  Duckworth.     A  Plea  for  the  Neurotic  Theory  of  Gout.     Brain,  III,  1  (1880). 

Ibid.  On  Lead  Impregnation  in  Relation  to  Gout.  St.  Bartholomew's  Hospital  Re- 
ports, 17,  249  (1881). 

Ibid.     On  Gout  Considered  as  a  Tropho-neurosis.     Brit.  Med.  Journ.  (1881),  1,  463. 

Ibid.     A  Treatise  on  Gout.     London  (1890). 

Ibid.     The  Pathology  of  Gout  (1900),  II,  571. 


Pathology  301 

the  importance  of  the  nervous  system  in  the  production  of  gout. 
They  have  not,  as  a  rule,  had  very  definite  notions  of  the  role  of 
the  nervous  system  in  causing  gout,  and  their  evidence  has  not 
generally  been  exceedingly  good. 

According  to  Latham,  gout  is  a  primary  neurosis,  but  uric  acid 
is  the  toxic  agent. 

In  his  earlier  writings,  Duckworth  calls  gout  a  tropho-neurosis, 
and  says  that  it  is  characterized  by  "  a  special  morbid  evolution 
of  nerve  force."  He  thinks  that  some  part  of  the  medulla  ob- 
longata is  specially  involved.  What  Duckworth  really  meant 
was  that  gout  is  due  to  faulty  metabolism,  and  this  is  what  he 
says  in  his  recent  writings.  There  is  no  structural  defect  in  the 
nervous  system  according  to  this  author. 

It  is  plain  that  no  definite  explanation  of  gout  has  yet  been 
given  that  is  correct.  We  know  that  in  gout  there  is  uric  acid 
in  solution  in  the  blood,  and  that  there  are  urate  concretions  in 
the  joints.  We  do  not  know  which  of  these  conditions  is  cause  or 
which  effect,  or  even  whether  they  are  related  as  cause  and  effect. 
They  may  both  be  due  to  a  common  cause.  We  have  criticised 
all  the  explanations  that  have  been  offered  to  explain  gout,  and 
have  not  stated  any  theory  of  our  own.  We  are  justified  in  this. 
More  data  is  necessary  concerning  the  metabolism  in  gout  before 
we  are  warranted  in  offering  any  definite  theory  of  the  cause  of 
gout.  The  humoral  theory  of  gout,  as  expressed  by  Minkowski, 
and  the  nervous  theory,  as  expressed  by  Duckworth,  approach 
each  other  in  the  indefinite  view  that  gout  is  due  to  some  sort  of 
faulty  metabolism.  This  is  as  near  a  correct  theory  of  gout  as 
we  have  so  far  attained.  The  view  of  W^atson,^  that  gout  is  a 
disease  of  bacterial  origin,  may  be  mentioned  for  the  sake  of  com- 
pleteness.    His  evidence  is  not  convincing. 

Cause  of  the  Acute  Attack  of  Gout 

According  to  Garrod,^  the  acute  attack  of  gout  is  due  to  a 
temporary  defect  in  the  kidneys  to  excrete  uric  acid,  whereby 
this  compound  accumulates  in  the  blood,  and  a  temporary  de- 
crease in  the  alkalinity  of  the  blood,  which  causes  the  uric  acid 
in  the  blood  to  precipitate.  The  pain  is  due  to  the  mechanical 
irritation  of  the  sharp  urate  crystals. 

>  C.  Watson.     Observations  on  the  Pathogenesis  of  Gout.     Brit.  Med.  Journ.  (1904),  68. 
2  A.  Garrod.     The  Nature  and  Treatment  of  Gout.     (1S95.) 


302      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Levison  ^  agrees  with  Garrod  in  the  view  that  an  acute  attack 
of  gout  is  due  to  the  deposition  of  urates  from  saturated  solution 
in  the  blood.  When  the  urates  are  deposited  slowly,  we  get 
chronic  gout.  Kittel/  too,  takes  the  view  that  the  pain  in 
gout  is  due  to  the  pressure  of  the  sharp  urate  crystals,  and 
that  when  these  concretions  are  slowly  formed  there  is  no 
pain. 

Senator,^  Rindfleisch,*  and  Roberts  ^  agree  with  Garrod  that 
the  pain  in  gout  is  due  to  the  mechanical  irritation  of  the  urate 
crystals. 

According  to  Jones,®  an  attack  of  gout  is  a  chemical  process 
of  oxidation  set  up  in  the  place  where  the  urates  are  accumu- 
lated, whereby  the  urate  is  oxidized  further  to  urea  and  car- 
bonates. 

Ebstein  ^  thinks  the  acute  attack  is  due  primarily  to  a  stasis 
of  the  lymph  stream  containing  urate  in  solution.  This  com- 
pound is  toxic,  and  causes  tissue  necrosis.  The  necrosed  tissue 
reacts  acid  and  causes  a  precipitation  of  the  acid  urate. 

Pfeiffer  ^  and  Aronsohn  ^  believe  that  the  deposition  of  urate 
precedes  the  acute  attack  of  gout.  The  latter  is  due  to  the  reso- 
lution of  the  urate  on  account  of  a  temporary  increase  in  the 
alkalinity  of  the  blood. 

We  have  already  discussed  the  evidence  on  which  these  authors 
base  their  theories,  so  that  it  will  not  be  necessary  to  show  again 
at  this  place  that  they  are  wrong.  We  have  seen  that  the  blood 
alkalinity  is  normal  in  gout,  at  least  according  to  titration  methods, 
and  we  know  that  an  increase  in  the  alkalinity  would  not  make 
the  blood  a  better  solvent  for  sodium  acid  urate. 

We  cannot  state  positively  that  the  pain  in  gout  is  not  due,  at 
least  in  part,  to  the  action  of  uric  acid  as  a  mechanical  irritant. 

*  F.  Levison.     The  Uric  Acid  Diathesis.     Transl.  by  L.  Scott.     London  (1884). 

^  M.  Levison.  Die  gichtischen  harnsauren  Ablagerungen  im  menschlichen  Korper. 
Leipzig  (1902),  3  Aufl. 

3  Senator.  Gicht.  Ziemssen's  Handbuch  der  speciellen  Pathologie  und  Therapie . 
Leipzig  (1875). 

"I  Rindfleisch.     Lehrbuch  der  pathologischen  Gewebelehre.     Leipzig  (1873).  3  Aufl. 

5W.  Roberts.  On  the  Chemistry  and  Therapeutics  of  Uric  Acid,  Gravel,  and  Gout. 
(Croonian  Lectures  for  1892.) 

^  H.  Jones.  Lectures  on  Some  of  the  Applications  of  Chemistry  and  Mechanics  to 
Pathology  and  Therapeutics.     London  (1867). 

'W.  Ebstein.     Beitrage  zur  Lehre  von  der  harnsauren   Diathese.     Wiesbaden  (1891). 

8  E.  Pfeiffer.     Die  Gicht  und  ihre  erfolgreich  Behandlung.     Wiesbaden  (1891),  2  Aufl. 

9  E.  Aronsohn.  Zur  Natur  und  Behandlung  der  Gicht  und  iiber  die  Bedeutung  der 
Emser  Wilhelmsquelle.     Deutsche  med.  Wochen.?chrift,  16,  381  (1890). 


Pathology  303 

According  to  Freudweiler  *  and  His,^  it  has  also  a  slight  toxic 
action.     The  pain  may  not  be  due  entirely  to  uric  acid. 

Hutchinson/  Duckworth/  and  von  Noorden  ^  have  maintained 
that  urate  concretions  are  not  always  found  in  persons  who 
have  suffered  from  an  acute  attack  of  gout,  and  that,  therefore, 
the  pain  and  inflammation  in  the  attack  is  not  due  to  the  urate. 
His  ^  and  Freudweiler  ^  have  shown  that  the  urate  may  be 
removed  by  phagocytes.  Hutchinson,  Duckworth,  and  von  Noor- 
den may  have  drawn  their  conclusions  from  the  observation  of 
cases  where  the  urates  had  been  removed  in  this  manner. 

Minkowski  has  suggested  that  the  nucleic  acid  of  the  phagoc3^tes 
may  dissolve  the  uric  acid.  The  increase  in  the  excretion  of  uric 
acid  after  the  onset  of  an  acute  attack  of  gout  may  be  due  to 
the  uric  acid  which  is  dissolved  by  the  phagocytes  and  excreted. 

It  is  plain  that  we  have  not  the  data  to  explain  the  cause  of 
the  acute  attack  of  gout  any  more  than  we  have  to  explain  the 
formation  of  the  concretions. 

Uric  Acid  Infarcts 

Concretions  containing  uric  acid  are  often  found  in  the  kidnej'S 
of  children  who  die  during  the  first  two  weeks  of  life.  Ebstein  ^ 
believed  the  uric  acid  to  be  in  the  form  of  sodium  acid  urate. 
According  to  FlensburgJ  the  concretions  contain  ammonium 
urate.  Reusing  ^  came  to  the  conclusion  that  the  uric  acid  is 
present  as  such,  and  not  in  the  form  of  a  salt. 

The  occurrence  of  these  infarcts  is  so  frequent  that  they  are  not 
considered   pathological   by   some   writers.     Salomonsen "   found 

1  M.  Freudweiler.  ExperimenteUe  Untersuchungen  liber  die  Entstehiing  der  Gicht- 
knoten.     Deutsche  Arch,  ftir  klin.  Medizin,  68,  155  (1900). 

2  W.  His.  Die  Ausscheidung  von  Harnsaure  im  Urin  der  Gichtkranken  mit  besonderer 
Beriicksichtigung  der  Anfallzeiten  und  bestimmter  Behandlungsmethoden.  Deut.sche 
Arch,  fiir  klin.  Medizin,  65,  156  (1900),  and 

Ibid.  Schicksal  und  Wirkungen  des  sauren  harn.^auren  Natrons  im  Bauch-  und  Gelenk- 
hohle  der  Kaninchen.     Deutsche  Arch,  fiir  klin.  Medizin,  67,  81  (1900). 

3  J.  Hutchinson.  On  the  Relation  which  Exists  between  Gout  and  Rheumatism. 
Trans.  Internat.  Med.  Congr.,  London,  II,  92  (1881). 

4D.  Duckworth.     A  Treatise  on  Gout.     London  (1890). 

5  C.  von  Noorden.     Lehrbuch  der  Pathologie  des  Stoffwechsels.     Berlin  (1893). 

^  W.  Ebstein.     Die  Natur  und  Behandlung  der  Harnsteine.     Wiesbaden  (1884). 

'  C.  Flensburg.  Studier  ofver  I'rinsyreinfarkten,  urinsedimentet  och  albuminurin 
hos  nyfodela.  Nord.  med.  .\rkiv.  (1894),  No.  9  and  No.  14.  Centralblatt  fiir  innere 
Medizin,   15,  965  (1894). 

*  H.  Reusing.  Beitrage  zur  Physiologie  des  Neugebnrnen.  Zeitschr.  fiir  Geburtshiilfe, 
und  Gyniikologie,  3.3,  36  (1895). 

^Salomonsen.     I'rinsyreinfarcthos  Nyfcidte.     Dissert.,  Copenhagen   (1859). 


304      The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

uric  acid  infarcts  in  140  cases,  and  no  infarcts  in  160  cases,  out  of 
304.  According  to  Spiegelberg/  infarcts  are  found  in  more  than 
half  the  children  dying  under  two  weeks  of  age.  Flensburg  ^ 
studied  twenty  cases  and  found  infarcts  in  every  case. 

In  accord  with  the  old  view,  the  infarcts  were  looked  upon  as 
indicating  low  oxidation  processes  in  the  first  few  days  of  life 
whereby  less  urea  and  more  uric  acid  are  formed  than  normally.^ 
They  are  now  generally  considered  simply  the  result  of  precipi- 
tation from  urine  which  is  highly  concentrated  in  uric  acid. 
Thus  Martin  and  Ruge,*  Flensburg,^  Schreiber,^  Reusing,^  Mares,^ 
and  Sjoquist  ^  found  the  excretion  of  uric  acid  very  high  in  the 
first  few  days  of  life.  Mares  found  that  |  per  cent  of  the  total 
nitrogen  of  young  infants  is  excreted  as  uric  acid.  This  fraction 
is  only  ^  per  cent  in  adults.  Reusing  found  the  ratio  of  uric  acid 
to  urea  from  1  :  1.5  to  1  :  6.5  during  the  first  few  days  of  life, 
an  exceedingly  high  ratio.  This  author  likewise  called  attention 
to  the  fact  that  the  infarcts  were  more  common  in  children 
naturally  fed  than  in  those  fed  artificially.  The  latter  get  much 
more  fluid,  and  therefore  the  urine  is  not  so  likely  to  become 
saturated  with  uric  acid.  The  quantity  of  urine  excreted 
in  twenty-four  hours  increases  rapidly  with  age  during  the 
early  days.  The  uric  acid  excretion  is  nearly  stationary  for  a 
while. 

The  uric  acid  excreted  by  infants  is  endogenous  uric  acid. 
There  are  no  purins  in  milk  food.  As  we  should  expect,  the 
amount  excreted  does  not  varj'  with  the  quantity  of  food,  accord- 
ing to  Reusing.     Schreiber  believes  with  Horbaczewski  that  the 

'  H.  Spiegelberg.  Ueber  den  Harnsaureeinfarct  der  Neugebornen.  Arch,  fiir  exp. 
Path.  u.  Pharm.,  41,  428  (1898). 

^C.  Flensburg.  Studier  ofver  Urinsyreinfarkten,  urinsedimentet  och  albuminurin 
hos  nyfodela.  Nord.  med.  Arkiv.  (1894),  No.  9  and  No.  14.  Centralblatt  fiir  innere 
Medizin,  15,  965  (1894). 

5  Vierordt.  Physiologie  des  Kindesalters  in  Gerhard's  Handbuch  der  Kinderkrank- 
heiten,  IV,  374. 

^Martin  und  Ruge.  Zeitschr.  fiir  Geburtshiilfe  und  Frauenkrankheiten,  1,  273 
(1875). 

^  E.  Schreiber.  Gicht.  Ueber  die  Harnsaure  unter  physiologischen  und  pathologi- 
schen  Bedingungen.     Stuttgart  (1899). 

^  H.  Reusing.  Beitrage  zur  Physiologie  des  Neugebornen.  Zeitschr.  fiir  Geburtshtilge 
und  Gynakologie,  33,  1  (1895). 

^  F.  Mares.  Sur  I'origine  de  I'acide  urique  chez  rhomme.  Arch,  slaves  de  biologie, 
III,  207  (1888),  also  Centralblatt  fur  die  med.  Wissenschaften.  26,  2  (1886). 

'  J.  Sjoquist.  N&,gra  analyser  ofvers  quafrets  fordelning  pa  urinsaurne  urinsyra  och 
ammoniak  i  urinen  hos  nyfodde  barn.  Nord.  Med.  Arkiv.  (1894);  Maly's  Jahresb. 
uber  die  Fortschritte  der  Thierchemie,  23,  245  (1893). 


Pathology  305 

high  uric  acid  in  young  infants  may  be  connected  with  the  large 
amount  of  leucocytes  in  the  blood  at  this  time,  but  this  has  not 
been  proved. 

Uric  Acid  in  Diseases  other  than  Gout 

We  have  already  spoken  of  the  uric  acid  in  the  blood  in  different 
diseases,  so  that  it  will  not  be  necessary  to  refer  to  that  point. 
We  have  likewise  given  an  account  of  the  relation  between  uric 
acid  in  the  urine  in  nephritis,  leukemia,  lead  poisoning,  liver 
cirrhosis,  and  atrophy,  and  phosphorus  poisoning.  Haig's 
erroneous  theories  of  the  relation  between  uric  acid  and  a  great 
many  diseases  have  been  shown  to  have  no  basis.  The  deter- 
mination of  uric  acid  by  the  Heinz  and  Hay  craft  methods,  and 
the  determination  of  the  purin  bodies  by  the  Kriiger-Wulff 
method,  gives  erroneous  results.  We  shall  not,  therefore,  consider 
results  determined  by  these  methods.  There  have  been  a  great 
many  determinations  of  the  uric  acid  in  diseases  other  than  gout, 
but  when  we  restrict  our  discussion  in  the  manner  indicated  in 
this  paragraph,  very  few  determinations  are  left.  The  results 
in  any  case  do  not  mean  much,  for  in  practically  none  of  the  cases 
has  the  diet  been  regulated,  and  we  know  that  the  exogenous 
uric  acid  can  vary  greatly  in    amount. 

In  pneumonia,  the  excretion  of  uric  acid  has  been  found  rather 
high  by  Kiihnau,^  Baftalowsky,^  and  Dunin  and  Nowaczck.^ 
Kaufmann  and  Mohr  ^  found  the  endogenous  uric  acid  high. 

The  old  view  that  the  uric  acid  excretion  is  decreased  in  diabetes 
must  be  erroneous.  Only  Camerer  '^  has  found  decreased  uric  acid 
excretion  by  an  accurate  method,  and  the  variation  from  normal 
was  but  little.     Gaethgens,"  Ebstein,^  Startz,*  Bischofswerder,**  and 

1  N.  Kiihnau.  Experimentelle  und  klinische  Untersuchungen  iiber  das  Verhaltniss  der 
Harnsaureausscheidung  zu  der  Leukocytose.     Zeitschr.  fiir  klin.  Medizin,  28,  534  (1895). 

-  B.  Baftalowsky.  Richter.  Ueber  Harnsaureausscheidung  und  Leukocytose.  Zeitschr. 
fur  klin.  Medizin,  27,  290  (1895). 

■'  T.  Dunin  und  St.  Nowaczck.  Ueber  Harnsaureausscheidung  bei  crouposer  Pneumonie. 
Zeitschr.  fiir  klin.  Medizin,  32,  1  (1897). 

<M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorper  und  zur  Pathologie  der 
Gicht.  II  Theil.  Ueber  AUoxurkorperausscheidung  unter  pathologischen  Verhaltni.^sen. 
Deutsche  Arch,  fur  klin.  Medizin,  74,  348  (1902). 

•''  Camerer.  Der  Gehalt  des  menschlichen  Urins  an  stickstoflFhaltigen  Ktirpern.  seine 
Aciditat:    die  Acidose  bei  der  Urinanalyse.     Tubingen  (1901). 

''  Gaethgens.  Ueber  Kreatinin  und  Harnsaureausscheidung  in  einem  todlich  endenden 
Fall  von  Diabetes  Mellitus.     Med.  Chem.  Untersuchungen  von  Hoppe-Seyler,  Heft  3. 

'  W.   Ebstein.     Zuckenharnruhs.     Wiesbaden   (1887). 

**  Startz.   Ueber  Harnsaureausscheidung  bei  Diabetes  Mellitus.   Freiburger  Dissert.  (1891). 

"  Bischofswerder.     Dissert.,    Bonn    (1896). 


306    The  Chemistry,  Physiology,  and  Pathology  of  Uric  Acid 

Jacoby  ^  have  found  the  uric  acid  excretion  high.  It  is  possible 
that  some  of  these  results  depend  upon  the  fact  that  the  diabetic 
diet  is  rich  in  meat,  which,  as  we  know,  contains  purin  bodies. 
Kaufmann  and  Mohr  ^  found  the  endogenous  uric  acid  high  in 
diabetes. 

Baftalowsky  ^  found  the  uric  acid  excretion  rather  high  in 
phthisis,  and  Camerer  *  found  it  high  in  a  case  of  acute  miliary 
tuberculosis.  Brandeburg  ^  and  Kiihnau  and  Weiss  ®  found 
normal  uric  acid  excretion  in  tuberculosis.  Topfer  ^  found  it 
sometimes  high  and  sometimes  low. 

Baftalowsky  ^  found  high  uric  acid  excretion  in  typhus.  Kiih- 
nau and  Weiss  ^  found    it   normal. 

The  results  of  Topfer  ^  and  Kiihnau  and  Weiss  ^  show  increased 
excretion  of  uric  acid  in  anemia.  Brandeburg  ^  obtained  normal 
results. 

Topfer  ^  found  rather  low  uric  acid  excretion  in  cases  of  cancer. 
Pott  *  found  normal  uric  acid  excretion  in  cases  of  cancer  of  the 
stomach  and  of  the  breast. 

According  to  Blumenthal,^  the  uric  acid  excretion  in  whooping 
cough  is  two  to  three  times  as  high  as  in  health. 

Sticker  ^"  found  the  uric  acid  excretion  high  in  hay  fever. 

Kiihnau  "  obtained  high  results  on  the  days  of  high  tempera- 
ture in  tertiary  intermittent  fever. 

'^  M.  Jacoby.  Ueber  die  Ausscheidung  der  stickstoflfhaltigen  Bestandtheile  beim  Dia- 
betes Mellitus.     Zeitsohr.  fur  klin.  Med.,  32,  557  (1897). 

^M.  Kaufmann  und  L.  Mohr.  Beitrage  zur  Alloxurkorper  und  zur  Pathologie  der 
Gicht.  II  Theil.  Ueber  Alloxurkorperausscheidung  unter  pathologischen  Verhaltnissen. 
Deutsche.  Arch,  fiir  klin.  Medizin,  74,  348  (1902). 

3  P.  Baftalowsky.  Richter.  Ueber  Harnsaureausscheidung  und  Leukocytose.  Zeitschr. 
fiir  klin.  Med.,  27,  290  (1895). 

*  W.  Camerer.  Zur  Lehre  von  der  Harnsaure  und  Gicht.  Deutsche  med.  Wochen- 
schrift,  17,  356  and  397  (1891). 

5  W.  Brandeburg.  Ueber  die  diagnostiche  Bedeutung  der  Harnsaure  und  Xanthinbasen 
im  Urin.     Berl.  klin.  Wochenschrift,  33,  137  (1896). 

*  W.  Kiihnau  und  F.  Weiss.  Weitere  Mittheilungen  zur  Kenntniss  der  Harnsaiire- 
ausscheidung  bei  leukocytose  und  hypoleukocytose  sowie  zur  Pathologie  der  Leukamie. 
Zeitschr.  fur  klin.  Med.,  32,  482  (1897). 

^  G.  Topfer.  Ueber  die  Relationen  der  stickstoffhaltigen  Bestandtheil  im  Harne  bei 
Carcinom. 

*  R.  Pott.  Stoffwechselanomalien  bei  einem  Fall  von  Stauungsicterus.  Pfliiger's 
Archiv,  46,  509  (1890). 

'  F.  Blumenthal.  Ueber  einige  Eigenschaften  des  Harns  bei  Keuchhusten.  Peters- 
burger  med.  Wochenschrift  (1893),  Beilage  3;  Maly's  Jahresb.  iiber  die  Fortschritte  der 
Thierchemie,  23.  546  (1893). 

'"  Sticker.  Der  Bostock's  Sommierkatarrh  (Heufieber).  Nothnagel's  Handbuch  (1896), 
4,  1,  108. 

"  Kiihnau.  Ueber  das  Verhalten  des  Stoffwechsels  und  der  weissen  Blutelemente  bei 
Blutdissolution.     Deutsche  Arch,  fur  klin.  Medizin,  58,  344  (1897). 


Pathology  307 

Beck  ^  found  normal  values  for  the  uric  acid  excretion  in  osteo- 
malacia. 

Colasanti  ^  has  confirmed  the  experiments  of  Marchand,' 
Lehmann,^  and  Rayer,''  showing  the  presence  of  uric  acid  in  the 
vomitus  in  cases  of  hysterical  anuria. 

Mandel  ^  found  some  relation  between  the  quantity  of  purin 
bases  in  the  urine  and  the  temperature  in  fever,  and  suggested 
that  these  may  help  to  bring  about  the  fever. 

It  will  be  well  to  state  here  that  there  has  never  been  shown 
any  relation  between  uric  acid  and  rheumatism.  Haig  believed 
that  gout  and  rheumatism  are  the  same  disease  and  due  to  uric 
acid.  Mort  believed  that  the  difference  between  these  two  dis- 
eases is  that  in  gout  crystalline  uric  acid  is  deposited  in  the  joints, 
and  that  in  rheumatism  his  so-called  "  kugel  "  or  amorphous 
spherical  urates  are  deposited.  We  have  seen  that  the  evidence 
offered  by  these  authors  is  of  no  value. 

It  is  generally  supposed  that  there  is  a  relation  between  cer- 
tain nervous  diseases  and  uric  acid.  The  idea  is  based  on 
the  experiments  of  Haig,  Ferguson,^  Krainski,^  and  Caro,**  who 
found  the  amount  of  uric  acid  excreted  proportional  to  the 
severity  of  the  attack  in  epilepsy;  to  the  experiments  of 
Herter  and  Smith/"  who  found  the  uric  acid  excretion  high  in 
severe  cases  of  neurasthenia,  and  to  the  experiments  of  Lange," 
who  found  mental  depression  associated  with  high  uric  acid  in 
the  blood.  Haig,  Ferguson,  and  Krainski  used  the  inaccurate 
Haycraft   method  in  determining  uric  acid,  and  Caro  used  the 

'  M.  Beck.  Ueber  das  gegenseitige  Verhaltniss  der  Stickstofifhaltigen  Substanzen  im 
Harne  bei  Osteomalacie.     Prager  med.  Woohenschrift,  19,  533  (1894). 

^  G.  Colasanti.  Ueber  das  Erbrechen  bei  Oligurie.  Moleschott's  Untersuchungen  zur 
Naturlehre  des  Menschen,  14,  428  (1892). 

3  R.  Marchand.  Ueber  Harnstoff  in  hydropischen  Flussigkeiten.  Muller's  Archiv 
fur  Anat.  und  Physiol.,  440  (1837). 

^Lehmann.     Physiol.  Chem.,  II  (1853). 

'Rayer.     Maladies  des  reins.     Paris  (1850). 

*  A.  Mandel.  The  Alloxuric  Bases  in  Aseptic  Fever.  Am.  Journ.  of  Physiol.,  10,  452 
(1904).  • 

^  J.  Ferguson.  Some  Remarks  on  Epilepsy.  The  Alienist  and  Neurologist,  14,  235 
(1893). 

*  N.  Krainski.  Untersuchungen  iiber  den  Stoffwechsel  bei  Epileptikern  und  zur  Path- 
ologie  der  Epilepsie.  Maly's  Jahresb.  iiber  die  Fortschritte  der  Thierchemie,  26,  770 
(1896). 

5  Caro.  Ueber  die  Beziehung  epileptischen  Anfalle  zur  Harnsaureausscheidung. 
Deutsche  med.  Wochenschrift,  26,  308  (1900). 

1°  C.  Herter  and  E.  Smith.  Observations  on  the  Excretion  of  Uric  Acid  in  Health  and 
Disease.     N.  Y.  Med.  .lourn.,  55,  617  (1892). 

^' Lange.     Cm   Periodiske   Depressionstilstande.     Cobenhaven    (1886). 


308    The  Chemistry,  Physiology ,  and  Pathology  of  Uric  Acid 

Heinz  method.  Levison  ^  has  repeated  the  work  of  Lange  and 
found  no  relation  between  uric  acid  in  the  blood  and  epileptic 
attacks. 

1  F.  Levison.     Ueber  das  Verhaltniss  zwischen  Depressionszustanden  und  Harnsaure. 
Hospitalstidende  (1896),  15,  from  Arch,  fiir  Verdauungskrankheiten,  2,  413  (1896). 


END 


INDEX  TO  SUBJECTS 


Absorption,  nuclein   and  purin  bodies,  149. 

guanin,  159. 
Aceton,  239. 
Acidity,  73,  74,  232. 
Acute  gout,  301. 
Adenin,  chemistry,  41. 

metabolism,  57. 

occurrence,  108. 

synthesis,  42. 

toxic  action,  261. 
Alcohol,  232,  249. 
Alkalies,  235,  241. 

effect  on  solubility  of  uric  acid  in  urine, 
229. 

effect    on  uric  acid  concretions  in  birds, 
239. 
Alkalinity  of  blood,  235. 

effect  of  hydrochloric  acid  on,  237. 

effect  of  sodium  carbonate  on,  237. 
Allantoin,  3,  4,  21,  22. 

effect  on  uric  acid  excretion,  180. 

in  dogs  and  cats,  155,  158,  159,  195. 

in  rabbits,  190. 

occurrence,  45. 
Alloxan,  3,  5,  23,  29,  47. 

in  rabbits,  190. 
Alloxanic  acid,  3. 
Alloxantin,  3,  24. 

in  rabbits,  190. 
Aloin,  239. 

Amidomalonylurea,  47. 
Amino-purins,  8,  11,  41. 
Ammonium  tartrate,  241. 
Anemia,  306. 
Antifebrin,  252. 
Antipyrin,  252. 
Anuria,  307. 

Aromatic  sulphates  in  gout,  283. 
Arsenic,  256. 
Atropin,  256. 
Autodigestion,  181. 

Bacterial  theory  of  gout,  301. 

Barbituric  acid,   46. 

Baths,  256. 

Beer,  232,  250. 

Benzoic  acid,  175. 

Birds,   nitrogenous   metabolism  in,  93. 

organ  of  formation  of  uric  acid  in,  94. 

synthesis  of  uric  acid  in,  96. 

uric  acid  concretions  in,  239. 

uric  acid  formed  by  oxidation,  102. 

uric  acid  in  urine  of,  92. 
Bladder  stones,  2. 
Blood,  alkalinity,  236,  272. 

presence  of  uric  acid  in,  270,  284. 

solubility  of  uric  acid  in,  235,  273. 

Caffein,  chemistry,  2,  5,  25,  36. 

metabolism,  162. 
Calcium  compounds,  effect,  229,  242,  255. 
Campheric  acid,  256. 
Cancer,  306. 

Cane  sugar,  toxic  action,  263. 
Carbohydrates,  184. 
Carbolic  acid,  239. 


Carbon  monoxide,  168,  256. 

Carlsbad  water,  229. 

Carnivora,  organ  of  decomposition  of  uric 

acid  in,  219. 
Cartilage,  as  seat  of  formation  of  uric  acid, 

214. 
Champagne,  250. 
Cherries,  171,  176. 
Chinatropin,  174. 
Chlorosis,  168,  169. 
Chlorpurins,  10. 
Chromate  of  potassium,  261. 
Cirrhosis  of  liver,  217. 
Citron,  171,  176. 
Cocoa,  166. 
Coffee,  166. 
Cognac,  250. 
Colchicum,  251. 

Concretions  of  uric  acid,  cause,  292. 
chemical  composition,  269. 
in  birds,  239. 
Constipation,  153. 
Creatinin,  233. 

Decomposition  of  uric  acid,  decreased,  290. 
in  the  body,  186. 
in  dogs  and  cats,  193. 
in  man,  200. 
in  rabbits,  188. 
in  vitro,  187. 
organ  of,  219,  223. 
to  allantoin,  195,  206. 
to  glycocoll,  199,  206. 
to  oxalic  acid,  198,  202. 
to  parabanic  acid,  alloxan,  and    allox- 
antin, 199. 

Eggs,  135. 

Emphysema,  169. 

Ems  water,  242. 

Endogenous  uric  acid,  119,  143. 

Epilepsy,  307. 

Fachinger  water,  229. 

Fat,  effect  on  uric  acid  excretion,  103. 

metabolism  in  gout,  279. 
Feces,  150. 
Fish,  142. 

Formaldehyde,  234. 
Formation  of  uric  acid,  in  gout,  284. 

organ  of,  207. 
Fruit,  271. 

Glycosuria,  283. 
Glycerin,  178. 
Glycocoll,  171,  191. 
Gout,  269. 

alkalinity  of  blood  in,  272. 

aromatic  sulphates  in,  283.  _ 

combination  of  uric  acid  in  urine  in,  78. 

in  hogs,  268. 

indican  in,  282. 

metabolism  in,  275. 

metabohsm  of  fat  in,  279. 

metabolism  of  nitrogen  in,  279. 

metabolism  of  phosphorus  in,  282. 


309 


310 


Index  to  Subjects 


Gout,  continued. 

metabolism  of  potassium  in,  282. 

metabolism  of  purin  bodies  in,  278. 

metabolism  of  uric  acid  in,  284. 

treatment,  48. 
Grapes,  171,  176. 
Guanin,  absorption,  159. 

chemistry,  4,  25,  43,  51. 

gout  in  hogs,  268. 

metabolism,  116,  158. 

occurrence,  4,  43,  108. 

toxic  action,  259,  264. 
Guano,  2. 

Hay  fever,  306. 

Herbivora,  organ  of  decomposition  of  uric 

acid  in,  223. 
Heteroxanthin,  30. 
Hippuric  acid,  171. 
Hydrazin  poisoning,  197. 
Hydrochloric  acid,  effect  on  alkalinity  of 

blood,  237. 
Hydrouracil,  180. 
Hypoxanthin,  chemistry,  40. 

metabolism,  102,  116,  154. 

occurrence,  4,  40,  108. 

toxic  action,  258. 

Imidazol,  7. 
Indican,  282. 
Infarcts,  303. 
Intermittent  fever,  306. 
Isobarbituric  acid,  179. 
Isodialuric  acid,  179. 
Isouric  acid,  80. 

Kidney,  diseases  of,  286. 

as  organ  of  formation  of  uric  acid,  207. 

poisons,  239. 
Kola  nut,  256. 

Lactic  acid,  177. 

Lead,  254,  288. 

Leucocytes,  119. 

Leukemia,  167,  168,  169,  212,  294. 

Liver,  215. 

Lithium  compounds,  229,  241. 

Lvcetol,  230. 

Lysidin,  230.  231.  232,  241,  244. 

Meat,  138,  141,  262. 
Mesoxalic  acid,  99. 
Mesoxalylurea,  47. 
Metabolism 

adenin,  157. 

caifein,  162. 

guanin,  158. 

fat  in  gout,  279. 

hypoxanthin,  154. 

in  gout,  175. 

methyl  purins,  162. 

nitrogen  in  gout,  165. 

paraxanthin,  165. 

purin  bases  in  gout,  278. 

theobromin,  164. 

theophyllin,  165. 

uric  acid,  160. 

uric  acid  in  gout,'  275. 

xanthin,  156. 
Methyl  guanin,  45. 
Methyl  purins,  preparation,  10. 

metabolism,  162,  165. 
Methyl  uracil,  179. 
Methyl  xanthin,  31 . 
Milk,  139. 
Monoureides,  45. 
rS^  as  source  of  uric  acid,  178. 
Monoxypurins,  8,  40. 
Murexan,  47. 
Murex-id,  3,  24. 


Muscles,  214.  "  "  "  " 

Muscular  activity,  132.  -"'T^x^-s^ 

Necrosis,  261. 
Nephritis,  208. 
Nervous  diseases,  307. 
Nervous  theory,  300. 
Neurasthenia,  307. 
Nitrogen  metabolism  in  gout,  165. 
Nitrouracil,  179. 
Nitrouracilic  acid,  179. 

Nucleic  acid,  chemistry  and  occurrence,  104, 
114,  153. 

effect  on  solubility  of  uric  acid,  235. 

metabolism,  112,  137. 
Nucleins,  chemistry,  and  occurrence,  104, 
114. 

effect  on  leucocj'tosis,  130. 

metabolism,  112,  134. 
Nucleoproteid,  chemistry    and    occurrence, 
104,  114. 

metabolism,  112. 

Omnivora,  organ  of  decomposition  of  uric 

acid  in,  223. 
Organ  of  formation  of  uric  acid,  207. 

of  decomposition  of  uric  acid,  219,  223. 
Osteomalacia,  307. 
Oxalic  acid,  23,  187. 

in  dogs  and  "cats,  198. 

in  man,  202. 

in  rabbits,  190. 

toxic  action,  239,  262. 
Oxaluric  acid,  3,  23,  46. 

in  rabbits,  190. 
Oxygen,  255. 

Pancreatic  disease,  153. 
Parabanic  acid,  3,  23,  46. 

in  dogs  and  cats,  199. 

in  rabbits,  190. 
Paraxanthin,  34. 

metabolism,  165. 

toxic  action,  259,  260. 
Pathology  of  uric  acid,  258. 
Phenacetin,  252. 
Phenol,  262. 
Phosphorus,  metabolism  in  gout,  282. 

poisoning,  131,  217. 
Pilocarpin,  255. 

Piperazin,  173,  230,  213,  232,  241,  244. 
Piperidine,  230,  232. 
Pneumonia,  305. 
Potassium,  compounds,  229,  242,  256. 

chromate,  173,  239. 

metaboUsm  in  gout,  282. 
Proteid,  relation  to  uric  acid,  166. 
Pseudoleukemia,  213. 
Pseudouric  acid,  4,  47,  179. 
Purin,  8,  12,  45. 
Purin  bases,  as  source  of  uric  acid,  112,  134. 

excretion  of,  125. 

metabolism,  154. 
Purons,  24. 
Purpuric  acid,  48. 

Quinic  acid,  171,  247. 
Qmnine,  253. 

Retention  of  uric  acid  in  gout,  286. 
Rheumatism,  307. 

Sulphates  in  gout,  283. 

Salicylic  acid,  175,  245. 

Salts,  244. 

Sarkin  (see  Hypoxanthin). 

Serpent  excrement,  2. 

Sidonal,  173,  176,  231,  239. 

Sodium  compounds,  229,  237,  242. 


Index  to  Subjects 


311 


Solubility  of  uric  acid  and  urates,  55. 

effect  of  drugs  on,  226,  235. 

in  blood,  273. 

in  urine,  71. 

in  water,  48. 

effect  of  acids  on,  51. 
Sperm,  effect  on  uric  acid  excretion,  136. 
Spermin,  255. 
Spleen,  211. 

Starvation,  130,  132,  143,  144. 
Strawberries,  171. 
Sublimate,  239. 
Synthesis  of  uric  acid, 

in  vitro,  9,  14. 

in  the  body,  171. 


Tannic  acid,  254. 

Tannin,  253. 

Tarasper  water,  243. 

Tea,  166. 

Tetracarbonimide,  24. 

Thallium,  256. 

Theobromin,  chemistry,  4,  5,  31,  51. 

metabolism,  164. 
Theophyllin,  33,  165. 
Thiopurins,  11. 
Theories  of  gout,  bacterial,  301. 

Bowlby,  300. 

Bunge,  299. 

chemical,  292. 

Croftan,  298. 

Ebstein,  296. 

Ewich,  299. 

Garrod,  293. 

Gore,  300. 

Haig,  295. 

Klemperer,  297. 

Kolisch,  298. 

Hutchinson,  300. 

Luff,  296. 

Mordhorst,  297. 

nervous,  300. 

von  Noorden,  297. 

Pfeiffer,  298. 

Ritter,  299. 

Roberts,  298. 

Roose,  300. 
Thymic  acid,  107,  235. 
Thymin,  20,  135,  179. 
Toxicology,  258. 
Toxic  action,  of 

adenin,  261. 

cane  sugar,  262. 

dextrose,  262. 

hypoxanthin,  258,  260. 

guanin,  259,  264. 

oxalic  acid,  262. 

paraxanthin,  259,  260. 

phenol,  262. 

potassium  chromate,  261. 

uric  acid,  260,  261,  264. 

xanthin,  258,  260,  264. 
Tri-amino-oxypyrimidin,  179. 
Tuberculosis,  306. 
Typhus,  306. 


Uracil,  16. 
Uramil,  47. 
Urates,  55. 

acid  urates,  56. 

"  kugel  urates,"  57,  58,  59. 

neutral  urates,  55,  56. 


Urates,  continued. 
quadriurates,  63,  66. 
in  solution,  48,  55. 
solubility  in  blood  serum,  58.  60. 
solubility  in  urine,  87. 
solubility  in  water,  .56,  60,  61. 
Urea,  233. 

from  uric  acid  in  body,  189,  193. 
Uric  acid : 

amorphous,  54. 
crystalline,  54. 
compounds  of,  53,  69,  71. 
constitution,  3,  5. 

decomposition,    in   vitro,  1,   2,   3    4     20 
24,  49,  187. 
by  micro-organisms,  21. 
in  body,  186. 
in  dogs  and  cats,  193. 
in  man,  200. 
in  rabbits,  188. 
organ  of,  219,  223. 
to  allantoin,  195,  206. 
to  allo.xan  and  alloxantin,  199. 
to  glycocoll,  199,  206. 
to  oxalic  acid,  198,  202. 
to  parabanic  acid,  199. 
to  urea,  193. 
derivatives,  28. 
determination,  27. 
effect  of  drugs  on  excretion  of,  120. 
excreted,  unchanged,  189,  193,  201. 
formation,  in  body,  103. 
in  birds,  94. 

from  cells  other  than  leucocytes,  131. 
from  leucocytes,  119. 
from  purin  and  nucleoproteid,  104, 149. 
from  proteid,  166. 
organ  of,  207. 
in  blood,  66,  88,  270,  273,  284. 
in  birds,  92. 
in  disease,  113,  121. 
in  mammals,  103. 
in  solution,  48,  51. 
in  starvation,  130,  132,  143,  144. 
metabolism,  92,  142,  160,  275. 
occurrence,  2,  12. 
preparation,  26. 
reduction,  12,  24. 
relation  to  other  purins,  25. 
solubility  in  blood,  273. 
in  urine,  71. 
in  water,  48. 
source  in  body,  103.  112. 
structural  constitution,  4,  5,  54,  55. 
synthesis,  in  birds,  96. 
in  the  body,  171. 
in  eggs,  147. 

in  the  new  born,  147,  148. 
in  ^'itro,  5. 
test,  27. 

toxic  action,  260,  261,  264. 
Uricedin,  131,  244. 
Urol,  174. 
Uropherin,  174. 
Uropherin  benzoate,  174. 
Urosin,  173. 

Urotropin,  233,  234,  255. 
Urotropinsalicylate,  174. 
Ursal,  174. 

Water,  effect  on  its  excretion,  244. 
Whiskey,  250. 
Whooping  cough,  306. 
Wine,  232,  250. 


INDEX  TO  AUTHORS 


Abeles,  88,  89,  198,  203,  208,  211,  215,  270. 

Adler,  281. 

Ach,  6,  10,  11,  15,  25,  28,  32,  33,  37,  38. 

Ackeren,  von,  288. 

Albanese,  30,  163,  164. 

Albu,  210,  279,  288,  289. 

Allen,  56. 

Altmann,  106. 

Andral,  293. 

Andr(5,  20. 

Andreasch,  163. 

Araki,  97,  153. 

Archette,  23. 

Arnstein,  73. 

Aronsohn,  273,  302. 

Aschoff,  267. 

Ascoli,  210,  219,  220,  224,  289. 

Aubert,  163. 

Auerbach,  198. 

Aujeszky,  240,  242. 

Autenrieth,  190. 

Axenfeld,  241. 

Badt,  276,  279. 

Baeyer,  4,  5,  47,  180. 

Baftalowsky,  121,  209,  305,  306. 

Baginsky,  29.  40,  44,  116,  1.54. 

Bain,  175,  176,  241,  243,  255,  271,  276,  277, 

279 
Baldi,'288. 
Bang,  105,  106,  109. 
Barclay,  294. 
Bordet,  248. 
Barreswill,  154. 

Bartels,  71,  168,  208,  213,  214,  275,  286. 
Baumann,  176. 
Baumgarten,  57. 
Beck,  307. 
Beckart,  268. 

Becquerel,  64,  209,  269,  286. 
Beebe,  250,  251. 
Behrend,  5,  7,  14,  22,  28,  49. 
Beilstein,  51. 
Bencke,  245. 
Bennecke,  115,  122,  267. 
Bendix,  152,  159,  189,  275. 
Bensch,  26,  27,  49,  55,  56. 
Berell,  114,  212. 
Bergell,  123,  127,  136. 
Bergmann,  2. 
Berlinblau,  96. 
B^lioz,  73. 
Bernard,  13,  154. 
Berthelot,  20,  54. 
BerthoUet,  282. 
Berzelius,  2,  51,  63,  172. 
Biesenthal,   62,    173,   230,    239,   240,    243, 

244. 
Binz,  120,  253. 
Biondi,  109. 
Bird,  54. 

Bischofswerder,  305. 
Blarez,  49. 

Blumenthal,  174,  176,  247.  306. 
Bockendahl,  212. 
Booker,  275,  282. 


Biittger,  54. 

Bohland,  118,  124,  129,  171,  175,  212,  241, 
252,  253,  254,  256. 

Bokav,  149. 

Bondzynski,  30,  125,  163,  164,  165,  212. 

Borrisow,  197. 

Bopshard,  112. 

Bouchard,  175,  254,  275,  282. 

Boucheron,  89. 

Bowlby,  266,  .^OO. 

Brand,  13. 

Brandeburg.  136,  142,  151,  215,  306. 

Braun,  275. 

Brassier,  112. 

Bresster,  252. 

Brown,  158,  159,  160,  196,  197,  253,  254. 

Brucke,  13. 

Brugnatelli,  3,  23. 

Bruhns,  41. 

Brunelle,  254. 

Bryk,  21. 

Buchheim,  203. 

Buttner,  242. 

Bugarsky.  74,  112. 

Bunge,  50,  51,  98,  139,  200,  204,  299. 

Buniva,  3. 

Burian,  8,  107.  108,  110,  119,  123,  133,  134, 
137,  138,  139,  140,  142,  144,  145,  146, 
147,  148,  149,  155,  156,  157,  15S.  159, 
160,  161,  162,  166,  182,  183,  185,  187, 
189,  192,  193,  194,  202,  208,  215,  218, 
220,    221.  224,  225,    244,    247. 

Busquet,  141. 

Byasson,  175,  245. 

Camerer,  50,  71,  73,  127,  136,  143,  145,  276, 

279,  280,  305,  306. 
Cammidge,  234. 
Cantani,  270,  275,  287,  290. 
Cap,  93. 

Carbone,  261,  265. 
Cario,  121,  143. 
Caro,  307. 
Casper,  231. 

Cavendish,  2.  , 

Caventon,  36. 
Cazeneuve,  20,  94. 
Cech,  93. 

Charcot,  270,  295. 
Chassevant,  219,  220. 
Chittenden,  114,  120,  121,  250,  252,  253. 
Chopin,  246. 
Chotzen,  140,  250. 
Chrzonszczewski,  95,  115. 
Chwostek,  169,  171. 
Cingolani,  21. 
Cippolina,  205,  224. 
Citron,  234. 
Clar,  242. 
Claus,  21,  190. 
Clemm,  35. 
Cloetta,  89,  211,  215. 
Cohn,  158,  192,  196. 
Cohnheim,  104. 
Coindet,  93. 
Colasanti,  89,  95,  307. 

313 


314 


Index  to  Authors 


Colemann,  J.,  16, 

Colemann,  W.,  235. 

Combemale,  252. 

Copeland,  293. 

Croftan,  189,  193,  222,  223,  225,  259,  260, 

265,  271,  278,  291,  298. 
Cruveilhier,  292. 
CuUen,  300. 

Damsch,  157. 

Daniel,  123. 

Dapper,  139,  241,  245. 

Dastre,  59. 

Davies,  145,  232. 

Davy,  14,  93. 

De  Filippi,  216. 

De  Jager,  73. 

De  la  Camp,  176,  248. 

De  la  Source,  20,  49. 

Del^pine,  72. 

Deniger,  69. 

Deniges,  27. 

Determeyer,  242. 

Dickinson,  208,  286. 

Dietrich,  28. 

Dolff,  254. 

Donath,  74. 

Donogany,  161,  240,  242,  250. 

Donn^,  63. 

Dostal,  126,  186,  209,  212,  278,  289,  298. 

Douglas,  130. 

Drabczyk,  126. 

Dragendorff,  164. 

Drechsel,  114. 

Drouin,  273. 

Drygin,  5. 

Duckworth,  203,  267,  282,  294,  300,  301, 

303. 
Dunin,  122,  305. 
Dunlop,  133,  199,  203,  204. 
Duvernoy,  63. 

Ebstein,  56,  57,  58,  59,  116,  157,  161,  171, 
189,  193,  212,  227,  239,  243,  257,  261, 
262,  264,  265,  266,  269,  283,  285,  287, 
296,  297,  300,  303,  305. 

Eckart,  255. 

Eckardt,  169. 

Eckstein,  54. 

Edwards,  128. 

Ehrlich,  278. 

Esbach,  203. 

Ewald,  174,  231,  249. 

Ewart,  300. 

Ewich,  299. 

Fahraens,  128. 

Farkas,  236. 

Faust,  178. 

Fawcett,  275. 

Fehling,  51. 

Feliziani,  78. 

Ferguson,  307. 

Filehne,  258,  259,  260. 

Finck,  46. 

Fischer,   4,  5,  6,  7,  8,  9,  10,  11,  12,  15,  16, 

24,  28,  29,  30,   31,  32,  33,  34,  35,  36,  37, 

38,  39,  40,  41,  43,  45,  54,  55. 
Fittig,  6. 
Flatow,  126,  210. 
Fleischer,  208,  212,  286,  287. 
Flensburg,  303,  304. 
Fodor,  209.  288,  289. 
Foerster,  178,  248. 
Folin,  141 ,  145. 
Forbes,  292. 
Formanck,  256. 
Fourcroy,  2,  3,  13,  92,  292. 
Fraenkel,  94,  121,  122,  236. 


Frerichs,  59,  112,  160,  167,  186,  188,  191, 

195,  199,  200,  206,  209,  286. 
Freudberg,  237,  266. 
Freudweiler,  161,  259,  263,  264,  266,  267, 

299,  303. 
Freund,  73. 
Frey,  121. 
Fr^zal    254. 

Fritzsc'h,  53,  54,  55,  64,  66. 
Furbringer,  201. 
Futcher,  277,  278,  280,  282,  287. 

Gabriel,  16. 

Gaethgens,  305. 

Gagho,  198. 

Gairdner,  270. 

Galdi,  152,  155,  212,  215. 

Galeoth,  152. 

Gallois,  193,  194,  201. 

Gardes,  122. 

Gardner    295 

Garrod, 'l3,  14,  88,  89,  102,  186,  201,  204, 

207,    208,    254,    270,  271,  272,  275,  286, 

288,    293,    294,    301. 
Gaucher,  254,  260. 
Gautier,  258. 
Generali,  264,  265. 
Genth,  133,  244. 
Gerard,  21. 
Gerhardt,  23,  36. 
Giacosa,  118,  212. 
Gies,  176. 
Gigli,  49. 

Gilardoni,  241,  244. 
Girandeau,  122,  124. 
Giunti,  203. 
Glaser,  251. 
Goldenberg,  79. 
Goldscheider,  129,  174,  249. 
Goldthwait,  124. 
Goodbodv,  231. 
Gore,  300. 
Gorsky,  241. 

Gorup-Besanez,  167,  209,  211,  286. 
Goto,  70,  91,  235. 

Gottlieb,  30,  125,  163,  164,  165,  212,  219. 
Grabe,"l74. 
Graves,  252. 
Grawitz,  231. 
Griffiths,  13. 
Grimaux,  5,  46,  47. 
Grossmann,  276,  283. 
Groves,  233. 
Guinti,  198. 
Goldberg,  76. 
Gumlich,  117,  135,  149. 
Gumprecht,  122,  126,  214. 
Gusserow,  46. 

Haeser,  250. 

Hagen.  146,  152. 

Hagenburg,  175,  248. 

Hager,  261,  265. 

Hahn,  216,  221,  222. 

Haig,  141,  161,  166,  175,  201,  232,  235,  236, 

241,  246,  260,  271,  295,  305,  307. 
Haiser,  111. 
Hall,  112,  144,  145,  149.  151,  153,  155,  159, 

202,  250,  259,  260,  261,  283. 
Halliburton,  167,  290. 
Hammarsten,  51,  106,  163,  213. 
Hammerbacher,  199. 
Hammond,  133. 
Hardy,  23. 
Haughton,  138. 
Heidenhain,  157,  264. 
HeiUgenthal,  121. 
Heintz,  64. 
Henderson,  128. 
Henle,  133. 


Index  to  Authors 


315 


Henry,  48,  49. 

Herringham,  14.5,  232,  233. 

Hermann,  138,  178,  184,  243,  2.50,  2.56. 

Herter,  81,  132,  246,  250,  307. 

Hess,  135,  140,  158,  166. 

Hildebrandt,  180. 

Hill,  5,  10. 

Hirschfeld,  140,  145. 

His,  50,  52,  53,  57,  58,  60,  66,  68,  69,  70, 
71,  77,  81,  82,  83,  91,  146,  152,  161, 
176,  233,  234,  242,  243,  248,  251,  252, 
255,  264,  266,  267,  277,  303. 

Hober,  75,  82.  236,  237. 

Hofmann,  114,  144,  165,  212,  239. 

Holland,  292. 

Honigman,  255. 

Hood,  295. 

Hope,  136,  140,  180,  244. 

Hopkins,  14,  26,  27,  136,  140,  180,  244. 

Hoppe-Seyler,  51,  97,  207. 

Hofmann,  73. 

Horbaczewski,  5,  12,  14,  97,  117,  118,  119, 
120,  121,  122,  124,  129,  130,  131,  138, 
172,  177,  178.  183,  185,  212,  216,  217, 
252,  253,  256,  304. 

Huber,  248,  249. 

Hugounenq,  20. 

Huiskamp,  109. 

Hupfer,  175,  176,  248. 

Huppert,  27,  28,  50,  126,  210. 

Husches,  244. 

Hutchinson,  300,  303. 

Ibrahim,  161. 
Inoko,  110. 
Isaac,  110. 

Jackson,  214,  216,  217. 

Jacoby,   123,  125,  127,  129,  131,   136,   219, 

220,  306. 
Jacubasch,  114,  168,  212. 
Jaff^,  93,  154. 
Jahns,  76. 

Jaksch,  von,  88,  89,  131,  20S,  249,  271. 
Jankowsky,  75,  82. 
Jerome,  136,  141. 
Jobst,  3,  36. 
Jones,  61,  65,  66,  67,  68,  72,  108,  109,  138, 

181,  182,  270,  282,  290,  293,  302. 

Kam,  132,  208,  210,  214,  287,  289. 

Kanera.  138,  178,  183,  184. 

Kanger,  194,  196. 

Kaufmann,  155,    156,    184,    276,    279,    281, 

282,  284,  288,  289,  305,  506. 
Kemptner,  243. 

Kerner,  116,  120,  137,  159,  253. 
Ivionka,  262,  291. 
Kittel,  302. 
Klemperer,  53,  69,  80,  81,  83,  88,  142,  198, 

203,   204,   205,   208,   233,   238,   244,   270, 

271,   272.  273,   274,   276,   277,   285,   291, 
^297 
Knieriem,  von,  26,  93. 
Kobler,  244. 
Kochann,  291. 
Koehne,  199. 
Koerber,  7. 
Kolisch,  126,  132,  186,  209,  212,  259,  260, 

278,  289,  298. 
Kollmann,  169,  255. 
Korner,  114,  169,  213. 
Kossa,  von,  239,  240,  262. 
Kossel,  34,  40,  41,  69,  105,  106,  107,  108, 

110,  112,  115.  117,  137,  147,  168,  235. 
Kostvtschew,  109. 
Kotak,  110. 
Kowarski,  89. 
Kowaleski,  98,  101,  103. 


Krafft,  255. 

Krainski,  .307. 

Krau.f,  114,  169,  171. 

Kreidl,  21,  220. 

Kruger,  21,  26,  30,  31,  .34,  40,  41,  45,  116, 
125,  128,  1.38,  1.52,  1.54,  1.55,  1.56,  157, 
158,  159,  164,  165,  185,  209,  215. 

Krukenberg,  14. 

Kuhnau,  122,  123,  126,  2.55,  .305,  306. 

Kumg^gawa,  120,  175,  245,  252,  2.53. 

Kurajeff,  105. 

Kusmanoff,  1.39,  244. 

Kutscher,  110,  119,  205. 

Landwehr,  212. 

Lang,  S.,  98,  182,  224. 

Lang,  K.  von,  174. 

Lange,  307. 

Laquer,  126,  132,  139,  140,  184,  210,  242, 

243,  244,  250,  256,  278,  279,  280,  288. 
Larrabee,  132. 
Latham,  247,  284,  300,  301. 
Laugier,  269. 
Laurent,  23. 
Lautemann,  172,  174. 
Laveran,  242. 
Laval,  133. 
Lazarus,  278. 
Leber,  2.50. 
Le  Conte,  13. 

Lecorche,  175,  246,  252,  272,  275,  282,  295. 
Lehmann,  63,  77,  112,  124,  133.  138,  163, 

164,  167,  168,  269,  272,  275,  307. 
Lepinos,  73. 
Leube,  115. 
Leva,  243. 
Leven,  166. 
Levene,  109,  110,  181. 
Levison,  288. 
Levison,  C,   127,  243,  246,   252,  253,   254, 

256. 
Le\ason,  F.,  234,  246,  254,  276,  285,  287, 

295,  297,  302,  308. 
Levison,  M.,  302. 
Lewandosky,  175,  246,  248. 
Lewin,  173,  174,  178,  247,  248. 
Leyden,  von,  174,  249. 
L'Heritier,  63,  269. 
Lichtenstein,  248,  249. 
Lieberkiihn,  94,  95,  208. 
Liebermann,  74. 
Liebig,  4,  6,  23,  24,  27,  29,  46,  47,  51,  64, 

112,  167,  168,  186,  200,  290,  293. 
Lieblein,  73,  131,  216,  221. 
Liebreich,  251,  252,  298. 
Likhatscheff,  262,  268. 
Lilienfeld,  107,  110. 
Linne,  171. 
Lipowitz,  64. 
Lippmann,  von,  112. 
Litten,  268. 
Liveing,  300. 
Lobisch,  234. 
Loewi,  128,   140,    146,    147,  148,  158.  160, 

173,  185,  197,  201,  202,  206,  220,  280. 
Lommel,  203,  204,  205. 
Lo  Monaco,  143,  144,  214,  242. 
Loye,  59. 
Liicke,  173. 
Ludwig,  26,  27,  245. 
Luff,  238,  267,  273,  274,  287,  296. 
Liithje,  135,  187,  205,  2.54,  285,  286,  28S. 
Liitze,  89. 
Lusini,  191,  192. 
Luzzato,  190,  191,  195,  199,  206. 

Mabery,  5,  10. 

Maccadam,  133. 

Mach,  von,  102,  103,  154. 


316 


Index  to   Authors 


MacMunn,  14. 

Magnus-Levy,  88,  128,  175,  208,  210,  212, 
214,  237,   270,   271,  272,  273,   276,   280, 

281,  283,  288,  289. 
Mairet,  252. 
Majert,  230. 
Makowiecki,  257. 
Malcolm,  123,  159. 
Malerba,  27. 
Malfatti,  211,  278. 

Maly,73, 163,  172,  175,  247,248.  • 

Mandel,  307. 

Marcet,  2,  29. 

Marchand,  269,  307. 

Mares,  121,   129,   130,  131,  139,   169,   170, 

214,  255,  304. 
Marfori,  203. 
Markow,  139. 
Markwald,  245. 
Marrot   245 

Martin'  210,'  276,  279,  288,  289,  304. 
Maschke,  24. 
Massen,  221,  222. 
Mathews,  105. 
Matignon,  54,  55,  66. 
Matthes,  125,  127,  213. 
Mattschersky,  173,  174. 
Mayer,  118,  127,  135,  249. 
Mazuyer,  293. 
McCrudden,  81. 
Medicus,  5,  6,  37. 
Meisis,  173,  230,  231,  240,  244. 
Meissl,  13. 
Meissner,  13,  27,  89,  93,  95,  96,  113,  114, 

155,  160,  173,  174,  184,  194,  195. 
Meldon,  270,  300. 
Melis-Schirru,  128,  131. 
Mendel,  158,  159,  160,  190,  196,  197,  214, 

216,  217,  253,  254. 
Mendelsohn,  M.,  62,  230,  231. 
Mendelsohn,  W.,  44,  268. 
Merriam,  20. 
Meyer,  93,  168,  174,  249. 
Michel,  73. 
Micko,  110,  112,  151. 
Miescher,  105,  107,  115. 
Millon,  242. 
Mills,  13,  204. 

Milroy,  93,  96,  98,  103,  123,  159. 
Minkowski,  46,  48,  70,  91,  96,  97,  98,  131, 

135,   136,   137,    142,   146,   148,   154,   157, 

158,   165,   177,   178,   180,   194,   195,  196, 

200,   206,   226,   235,   261,   267,   268,   269, 

290,  294,  300,  303. 
Mitscherlich,  3,  48,  201. 
Mittelbach,  13. 
Mochizuki,  110,  136. 
Mohr,   155,   156,   184,  205,  276,  279,   281, 

282,  284,  288,  289,  305,  306. 
Monari,  110. 

Montessier,  132. 

Moore,  287. 

Mordhorst,  57,  77,  90,   91,  266,  268,   297, 

307. 
Moritz,  24. 
Morkowin,  105. 
Mortessier,  256. 
Moscatelli,  46. 
Mosler,  114,  169,  213,  245. 
Moss,  242,  252. 

Miinzer,  127,  131,  168,  216,  256. 
Mulder,  5,  180. 
Muller,  294. 
Munch,  242. 
Munk,  59,  178. 
Murchison,  297. 
Murri,  290. 
Mylius,  174,  249. 

Naegeli,  73. 


Naunyn,  46,  89,  171. 

Neisser,  264. 

Nencki,  21,  89,  116,  131,  137,  154,  156,  169, 

216,  220,  221,  222. 
Nernst,  74. 
Neubauer,  27,  28,  110,  150,  160,  167,  188, 

191,  200,  221,  222. 
Neumann,  69,  106,  109,  112. 
Neumayer,  229,  232,  233,  251. 
Neumeister,  2,  51,  213,  217,  294. 
Neusser,  124,  278. 
Nicolaier,  57,  58,  71,   157,   161,   175,   189, 

193,  234,  248,  261,  264,  265. 
Nicolais,  50. 
Noel-Paton,  252,  255. 
Noorden,  von,  91,   143,  210,  227,  229,  249, 

266,  289,  294,  297,  303. 
Nowaczek,  122,  305. 

Okerblum,  31,  110. 

Oliviero,  73. 

Ord,  58,  285,  300. 

Orgler,  79,  135,  139,  184,  234,  255. 

Ortowski,  173,  230,  231,  234,  240. 

Osgood,  124. 

Oudry,  2,  36. 

Pace,  127,  130,  136,  141,  166,  211,  212,  241, 

253,  255,  289. 
Paget,  300. 
Painter,  124. 
Pal,  258,  259. 
Palmer,  168,  256. 
Panum,  170. 
Parker,  151,  153. 
Parkes,  114,  212,  282,  290. 
Parkinson,  292. 
Partridge,  182. 
Paschkis,  258,  259. 
Paton,  133. 

Paul,  50,  51,  52,  53,  77,  81. 
Pawlinoff,  90,  95,  96,  115. 
Pawlow,  131,  216,  221,  222. 
Pearson,  2,  13,  292. 
Pecile,  29,  43. 
Pekelharing,  110. 
Pelletier,  2,  36. 
Penzoldt,  212. 

Petrc^n,  88,  89,  150,  151,  215,  272. 
Pettenkofer,  von,  114,  170. 
Pfaff,  259. 
Pfeiffer,  57,  59,  67,  68,  78,  80,  81,  83,  90, 

229,   247,   249,  265,  266,   273,   276,   280, 

285,  298,  .302. 
Pfeil,  141,  277. 
Philips,  5. 
Pick,  217,  221,  222. 
Pickardt,  89. 
Pierallini,  203. 
Plocz,  105. 

Poduschka,  160,  195,  197,  206. 
Poggendorf,  51. 
Pohl,  255. 

Pohl,  195,  197,  198,  222. 
Pope,  122,  127,  136. 
Popoff,  149. 
Posner,  77,  79. 
Pott,  234,  306. 
Pouchet,  40,  43,  46. 
Pribram,  294. 
Prior,  120,  253. 
Proust,  63. 

Prout,  2,  3,  13,  46,  48,  63,  71,  92. 
Putnam,  259. 

Quevenne,  63,  64. 

Raaschou,  109. 
Rabuteau,  203. 
Rachford,  259. 


Index  to  Authors 


317 


Ralfe,  290. 

Ranke,  H.,   113,   114,   119,   120,   123,   138, 

211,  253,  270,  275. 
Ranke,  J.,  139,  144,  169. 
Ransome,  251,  252. 
Ranvier,  267. 
Rayer,  293,  307. 
Reach,  277. 
Reichardt,  212. 
Reinke,  112. 
Reiss,  171. 

Reizenstein,  126,  210. 
Rendu, 290. 
Reusing,  303,  304. 
Rhorer.  74,  75,  82. 
Richet,  219,  220. 

Richter,  118,  125,  129,  137,  173,  239,  253. 
Rieder,  129. 
Riehl,  263,  267. 
Ries,  249. 

Rindfleisch,  267,  302. 
Ritter,  79,  80,  81,  84,  229,  256,  299. 
Roberts,  58.  59,  60,  61,  62,  66,  67,  68,  72, 

79,  81,  90,  271,  273,   288,   294,  298,  299, 

302. 
Robin,  71,  132,  252,  256. 
Robiquet,  2,  36. 
Rochleder,  4,  36. 
Rockwood,  133,   134,  145,  146. 
Rodewald,  112. 
Rodier,  269. 
Roeder,  16. 
Rohmann,  94,  121. 
Rommel,  210,  289. 
'Roose,  300. 
Roosen,  5,  14,  49. 
Rosemann,  250. 
Rosenfeld.  79,  135,  138,  140,  184,  229,  233, 

234.250,251,255. 
Rosengarten,  5. 
Rosenheim,  55,  57,  68,  86,  228,  232,  234, 

238. 
Rosenstein,  59. 
Rosin,  291. 
Rest,  163,  164,  165. 
Rotter,  203. 
Rtidel,  51,  69,  71,  233. 
Ruga,  304. 
Rung,  7. 
Runge,  2. 
Ruppel,  152. 


Sabrez^s,  254. 

Salaskin,  98,  101,  103. 

Salfeld,  174,  249. 

Salkowski,  13,  26,  27,  40,  72,  112,  113,  115, 

118,  126,   150,  159,   175,   176,   181,   187, 

189,  190,   193,  194,   195,  196,  199,  204, 

205,  206,  210,  211,  216,  241. 
Salom^,  246. 
Salomon,  13,  29,  30,  31,  34,  40,  44.  45,  89, 

112,   114,   115,   116,   118,   154,   156,  205, 

211,   216,   270,   271. 
Salomonsen,  303. 
Scheele,  1,  13,  20. 
Schenck,  205. 
Schenk,  109.  182. 

Scherer,  4,  29,  40,  64,  65,  66,  110,  113,  211. 
Schetelig,  78,  124. 
Scheube,  72. 
Schilling,  56. 
Schimanski,  94. 
Schindlcr,  41,  44,  202. 
Schittenhelm,  110,  150,  151,  152,  153,  154, 

157,  158,  159,  182,  189,  213,  215,  224,  251, 

275. 
Schlayer,  248. 
Schlieper,  4,  180. 
Schlunk,  46. 


Schmidt,  62,  152,  2.30,  244. 

Schmidt,  J.,  12S,  138,  155,    156,    157,    158, 

159 
Schmidt,  P.,  164,  165. 
Schmidt-Mijlheim,  111. 
Schmidt-Nielson,  111. 
Schmiedeberg,  107,  110,  200,  2.59,  200. 
Schmoll,  91,   135,   136,   140,   158,   166,  210, 

274,  276,  277,  279,  280,  281,  282,  289. 
Schneider,  164. 
Schondorff,  219,  220,  244. 
Scholtz,  24. 
Schreiber,   13,  88,   89,   128,    139,   143,   144, 

145,   160,   175,  230,  233,  243,  244,  246, 

248,  250,  262,  266,  288,  296,  304. 
Schroder,  von,   21,  89,  93,  95,  97. 
Schroter,  110. 
Schultens,  63. 
Schultz,  112,  139,  249. 
Schultzer,  114,  174. 
Schulz,  129. 
Schur,   110,   123,   137,   139,   141,   142,   144, 

145,   146,   147,   148,    149,    155,   156,   1.57, 

158,   159,   160,   161,   162,   166,  185,   187, 

189,   192,   193,   194,  202,  208,   220,   221, 

244. 
Schurz,  212. 
Schutzenkwer,  163,  165. 
Scudamore,  282. 
See,  246. 
Seegen,  245. 
Seeman,  119. 
Senator,  115,  170,  302. 
Serullas,  3. 
Sestini,  F.,  21. 
Sestini,  L.,  21. 
Severin,  243. 

Shepard,  13,  27,  173,  174. 
Sherman,  133,  140. 
Shorey,  112. 

Sieber,  21, 116,  137,  154,  156,  169,  220. 
Simon,  54. 
Singer,  81,  246. 

Siven,  128,  132,  141,  142,  145,  148,  185,  215. 
Sjoquist,  304. 
Smale,  50,  51,  76,  77. 
Smith,  132,  246,  250,  307. 
Smith-Jerome,  180. 
Soetbeer,  161,  273,  277,  283. 
Sommerfeld,  209. 
Speck,  133. 

Spiegelberg,  194,  264,  304. 
Spilker,  243. 
Spiro,  129. 

Spitzer,  118,  213.  216,  219,  294. 
Sprague,  243,  269. 
Stadeler,  21,  110,  195,  220. 
Stadelmann,  242. 
Stadthagen,  29,  40,  98,  116,  117,  137,  159, 

160,  170,  197,  209,  260,  288. 
Stahl,  300. 
Startz,  305. 
Steinberg,  114. 
Stejskal,  126. 
Stekel,  290. 
Stenhouse,  4,  36. 
Sternfeld,  174.  249. 
Steudel,  106,  107,  108,  178,  179,  180. 
Sticker,  122,  169,  212,  213,  216,  255,  256, 

306. 
Stokvis,  95,  160,  200,  211,  215,  219,  223,  282. 
Stockmann,  133. 
Stradomskv,  204,  205. 
Strahl,  94,  95,  208. 
Strassburger,  152. 

Strauss,  77,  141,  154,  233,  244,  270,  273,  279. 
Strecker,  4,  5,  10,  21,  26,  29,  32,  36,  40,  44, 

110,  172. 
Strohmer,  13. 
Stroux,  127,  252,  253,  256. 


318 


Index  to  Authors 


Stuve,  214. 
Sundwik,  22.  192. 
Surmont,  254. 
Swain,  194,  195,  199. 
Sydenham,  293. 

Tafel,  24,  25. 

Talamon,  246. 

Taltavall,  176. 

Tanago,  234. 

Tanszk,  246,  252,  253. 

Taylor,  136,  166,  252. 

Ten  Gate,  277,  282,  291. 

Tereg,  124. 

Thierfelder,  113,  114. 

Thomson,  2,  13,  92. 

Thudicum,  34,  40. 

Thurm,  28. 

Tibald,  249. 

Tichborne,  272. 

TichomirofE,  147. 

Todd,  293. 

Topfer,  73,  306. 

ToUens,  55,  152,  234. 

Traube,  15,  17. 

Tritschler,  198,  203,  204,  205. 

Tscherwinsky,  178. 

Tuczek,  130,  143. 

Tunicliffe,  57,  68,  86,  228,  232,  234,  238. 

Uhle,  114. 

Ulrici,  175,  246,  248,  254. 

Ulpiani,  21. 

Umber,  120,  136,  139,  242,  252,  255. 

Underhill,  197. 

Unger,  43. 

Ure,  293. 

Ury,  151. 

Van  Ackeren,  209. 

Vas,  246,  252,  253. 

Vauquelin,  2,  3,  13,  92. 

Verdeil,  71. 

Vicario,  61. 

Vierordt,  304. 

Virchow,  44,  113,  167,  211,  260. 

Vogel,  27,  28,  50.  209,  241,  243,  273,  276, 

279,  280,  281,  284,  289. 
Vogt,  124,  277,  279,  281,  282,  287. 
Voit,  73,  114,  120,  170. 

Waage,  76. 


Wagner,  208,  286. 

Waldvogel,  128,  139,  143,  144,    145,    160, 

175,  233,  246,  248,  277,  282. 
Wallach,  7. 
Warnecke,  27,  68. 

Watson,  272,  273,  277,  280,  282,  301. 
Weber,  234. 
Weidner,  246. 
Weinschenk,  25. 
Weintraud,   118,   126,   130,   134,   135,   136, 

150,   151,   160,   161,  177,  201,  208,  210, 

215,231,271,289. 
Weiske   29 
Weiss,  126,128,  135,  136,  158,  160,  171,  172, 

173,   174,   177,   184,   201,  243,  247,   250, 

254,  255,  306. 
Wells,  300. 
Wetzlar,  63. 
Wey,  127. 
Wheeler,  20,  23. 
Whipple,  110. 
White,  190,  196,  197. 
Whitehouse,  253. 
Wiener,  92,  99,  102,  103,  118,  140,  143,  178, 

181, 183, 191, 192, 193,  205,  213,  216,  217, 

218,  219,  220,  221,  224,  225,  285,  291. 
Williamson,  124. 
Willis,  64. 
Winternitz,  181. 
Wislicenus,  7. 
Wittich,  von,  90,  92. 
Wohler,  3,  20,  23,  24,  27,  29,  46,  47,  51,  112, 

160,   167,   171,   172,   174,   186,   188,   191, 

198,  199,  200,  206. 
Wohlgemuth,  109. 
Wolf,  272. 

Wollaston,  2,  92,  236,  292. 
Wosresensky,  4,  31. 
Wulfif,  26,  117,  125,  209. 
Wurzer,  269. 


Zabelin,  51,  160,  193,  199. 

Zalesky,  93,  94,  95,  131,  216. 

Zaudy,  230,  233,     243,  246,  262,  263,  296. 

Zagari,  127,  130,  132,  136,  141,  166,  211, 

212,  241,  253,  255,  276,  280,  289. 
Zerner,  75,  79. 
Ziegler,  268. 
Ziesig,  244. 
Zillessen,  97. 
Zulzer,  126,  210,  278,  289. 


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